UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, DC 20549

SCHEDULE 13D

Under the Securities Exchange Act of 1934

(Amendment No. 3)*

OPKO Health, Inc.

(Name of Issuer)

Common Stock, $0.01 par value

(Title of Class of Securities)

301610101

(CUSIP Number)

Kate Inman

4400 Biscayne Blvd.

Suite 1180

Miami, FL 33137

(305) 575-4138

(Name, Address and Telephone Number of Person Authorized to Receive Notices and Communications)

March 8, 2013

(Date of Event which Requires Filing of This Statement)

If the filing person has previously filed a statement on Schedule 13G to report the acquisition which is the subject of this Schedule 13D, and is filing this schedule because of §§ 240.13d-1(e), 240.13d-1(f) or 240.13d-1(g), check the following box  ¨.

The information required on the remainder of this cover page shall not be deemed to be “filed” for the purpose of Section 18 of the Securities Exchange Act of 1934 (“Act”) or otherwise subject to the liabilities of that section of the Act but shall be subject to all other provisions of the Act (however, see the Notes).

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This Amendment No. 3 (the “Amendment”) amends and supplements the statement on Schedule 13D filed on February 14, 2008, as amended by Amendment No. 1 to the Schedule 13D filed on August 21, 2008, as amended by Amendment No. 2 to the Schedule 13D filed on October 1, 2009 (together, the “Original Schedule 13D”), by Jane Hsiao, Ph.D. (“Dr. Hsiao”), The Chiin Hsiung Hsiao Family Trust A (“Trust A”), The Chiin Hsiung Hsiao Family Trust B (“Trust B”), and Hsu Gamma Investment, L.P. (“Hsu Gamma”). This Amendment is filed pursuant to the Joint Filing Agreement executed by the reporting persons listed on the cover pages to this Amendment. (Exhibit 1 to Amendment No. 1 to the Schedule 13D filed on August 21, 2008 is hereby incorporated by this reference.)

Item 3 is amended by adding the following paragraphs to the end of the item:

Dr. Hsiao acquired 1,220,000 shares of Common Stock, for investment purposes, in a series of transactions from October 2, 2009 to March 21, 2013, at prices ranging from $3.60 to $4.73 per share for an aggregate purchase price of $4,410,314, including without limitation 1,200,000 shares of Common Stock in a private transaction with Chung Chia Company Limited (“Chung Chia”) on October 5, 2011 at $3.60 per share, for an aggregate purchase price of $4,320,000. The source of funds used in all transactions from October 2, 2009 to March 21, 2013 was Dr. Hsiao’s personal funds.

Hsu Gamma acquired 733,000 shares of Common Stock, for investment purposes, in a series of transactions from October 2, 2009 to March 21, 2013, at prices ranging from $3.55 to $3.75 per share for an aggregate purchase price of $2,708,750, including without limitation 533,000 shares of Common Stock in a public offering from the Issuer at the public offering price of $3.75 per share. Hsu Gamma also acquired 806,450 shares of Common Stock upon the conversion of 80,645 shares of Series D Preferred Stock on March 8, 2013. The Series D Preferred Stock was acquired for investment purposes on September 18, 2009, in a private placement with the Issuer, which closed on September 28, 2009. The source of funds used in all transactions from October 2, 2009 to March 21, 2013 was Dr. Hsiao’s personal funds.

Item 4 is amended by adding the following paragraphs to the end of the item:

Dr. Hsiao acquired 1,220,000 shares of Common Stock, for investment purposes, in a series of transactions from October 2, 2009 to March 21, 2013, at prices ranging from $3.60 to $4.73 per share, of which 20,000 shares were purchased on the open market and 1,200,000 shares were purchased from Chung Chia in a private transaction pursuant to a stock purchase agreement (the “Chung Chia Agreement”) dated October 5, 2011 at $3.60 per share.

Hsu Gamma acquired 733,000 shares of Common Stock, for investment purposes, in a series of transactions from October 2, 2009 to March 21, 2013, at prices ranging from $3.55 to $3.75 per share, of which 200,000 shares were purchased on the open market and 533,000 shares were purchased on March 9, 2011 in a public offering from the Issuer, which closed on March 14, 2011, at the public offering price of $3.75 per share. Hsu Gamma also acquired 806,450 shares of Common Stock upon the conversion of 80,645 shares of Series D Preferred Stock on March 8, 2013. The Series D Preferred Stock was acquired for investment purposes on September 18, 2009, in a private placement with the Issuer, which closed on September 28, 2009.

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In the last 60 days prior to the filing of this Amendment No. 3, Hsu Gamma acquired 806,450 shares of Common Stock upon the conversion of 80,645 shares of Series D Preferred Stock on March 8, 2013. The Series D Preferred Stock was acquired for investment purposes on September 18, 2009, in a private placement with the issuer, which closed on September 28, 2009, whereby Hsu Gamma acquired the shares of Series D Preferred Stock for $24.80 per share.

Item 5 is deleted in its entirety and replaced with the following text:

Dr. Hsiao may be deemed to beneficially own 28,480,174 shares of Common Stock, which consist of (i) 1,000,000 shares of Common Stock held by Trust A, (ii) 1,000,000 shares of Common Stock held by Trust B, (iii) 3,904,250 shares of Common Stock held by Hsu Gamma, (iii) vested warrants to purchase 201,613 shares of Common Stock held by Hsu Gamma, (iv) vested warrants to purchase 2,936,580 shares of Common Stock held individually, (v) options to acquire 1,537,500 shares of Common Stock, which are exercisable within 60 days of March 21, 2013 held individually, and (vi) 17,900,231 shares of Common Stock held individually. The 28,480,174 shares of Common Stock beneficially owned by Dr. Hsiao constitute 8.7 % of the Issuer’s outstanding shares of Common Stock, based upon 324,257,735 shares of Common Stock outstanding as of March 8, 2013, and calculated in accordance with Rule 13d-3. Dr. Hsiao has sole voting and dispositive power over 28,480,174 shares of Common Stock.

Trust A beneficially owns 1,000,000 shares of Common Stock, which constitute 0.3% of the Issuer’s outstanding shares of Common Stock, based on 324,257,735 shares of Common Stock outstanding as of March 8, 2013, and calculated in accordance with Rule 13d-3. Dr. Hsiao is the sole trustee of Trust A and holds sole voting and dispositive power with respect to the 1,000,000 shares of Common Stock held by Trust A.

Trust B beneficially owns 1,000,000 shares of Common Stock, which constitute 0.3% of the Issuer’s outstanding shares of Common Stock, based on 324,257,735 shares of Common Stock outstanding as of March 8, 2013, and calculated in accordance with Rule 13d-3. Dr. Hsiao is the sole trustee of Trust B and holds sole voting and dispositive power with respect to the 1,000,000 shares of Common Stock held by Trust B.

Hsu Gamma beneficially owns 4,105,863 shares of Common Stock, which include vested warrants to purchase 201,613 shares of Common Stock and constitute 1.3% of the Issuer’s outstanding shares of Common Stock, based on 324,257,735 shares of Common Stock outstanding as of March 8, 2013, and calculated in accordance with Rule 13d-3. Dr. Hsiao is the general partner of Hsu Gamma and holds sole voting and dispositive power with respect to the 4,105,863 shares of Common Stock held by Hsu Gamma.

Dr. Hsiao is a member of The Frost Group, LLC, which holds 15,490,546 shares of Common Stock and vested warrants to purchase 4,796,158 shares of Common Stock. Dr. Hsiao disclaims beneficial ownership of the shares of Common Stock and warrants held by The Frost Group, LLC.

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For information regarding transactions effected during the past 60 days prior to the filing of this Amendment No. 3, see Item 4 above.

Except as described herein, no other person is known by any Reporting Person to have the right to receive or the power to direct the receipt of dividends from, or the proceeds from the sale of, any shares of the Issuer beneficially owned by them.

Item 6 is amended in its entirety and replaced with the following text:

See Item 4 regarding the Stock Purchase Agreement, Second Stock Purchase Agreement, the Psilos Securities Purchase Agreement, the Third Stock Purchase Agreement, the V-Sciences Agreement, CRG Agreement, the Kennedy Agreement, the Fourth Stock Purchase Agreement, Warrant Agreement, and the Chung Chia Agreement.

Except as identified herein, the Reporting Persons do not have any contracts, arrangements, understandings or relationships (legal or otherwise) with any person with respect to any securities of the Issuer, finder’s fees, joint ventures, loan or option agreements, puts or calls, guarantees of profits, or the division of profits or losses.

Item 7 is amended by adding the following paragraphs to the end of the item:

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SIGNATURES

After reasonable inquiry and to the best of my knowledge and belief, I certify that the information set forth in this statement is true, complete and correct.

EXHIBIT 8

SECURITIES PURCHASE AGREEMENT (this “Agreement”) dated as of October 5, 2011, among Chung Chia Company Limited (the “Seller”) and the parties set forth on Schedule I hereto (the “Purchasers”).

RECITALS

WHEREAS, the Seller currently holds a certificate representing 9,500,000 of the issued and outstanding shares of the Common Stock, $0.01 par value, of OPKO HEALTH, INC., a Delaware corporation (the “Corporation”); and

WHEREAS, the Seller desires to sell to the Purchasers and the Purchasers desire to purchase from the Seller, an aggregate of 9,500,000 of such shares (the “Purchased Securities”) in amounts set forth opposite such Purchaser’s name on Schedule I attached hereto, for a purchase price of $3.60 per share of Purchased Security (the “Purchase Price”).

NOW THEREFORE, in consideration of the mutual promises contained herein and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the parties hereto hereby agree as follows:

Section 1. Purchase and Sale of the Purchased Securities.

Subject to the terms and conditions hereof, the Seller hereby agrees to sell to each Purchaser, and each Purchaser hereby irrevocably agrees to purchase from the Seller, all of the Seller’s right, title and interest in, to and under, the Purchased Securities in amounts set forth opposite such Purchaser’s name on Schedule I attached hereto.

Section 2. Closing.

The closing of the transaction (the “Closing”) shall take place on or about October 5, 2011, or as soon thereafter as is possible.

Section 3. Deliveries.

A. Seller Deliverables. At the Closing, upon delivery of the Purchase Price, the Seller shall deliver to each Purchaser:

B. Purchaser Deliverables. At the Closing, each Purchaser shall deliver to the Seller:

Section 4. Representations, Warranties and Acknowledgements of the Seller.

The Seller hereby represents and warrants to each Purchaser, as follows:

A. Due Authorization; Due Execution; No Conflicts. This Agreement has been duly executed and delivered by the Seller and is the valid and binding obligation of the Seller, enforceable in accordance with its terms. The execution, delivery and performance by the Seller of this Agreement does not (a) violate any provision of law, statute, rule or regulation applicable to the Seller or any ruling, writ, injunction, order, judgment or decree of any court, administrative agency or other governmental body applicable to the Seller or (b) conflict with or result in any breach of any of the terms, conditions or provisions of, or constitute (with due notice or lapse of time or both) a default (or give rise to any right of termination, cancellation or acceleration) under, or result in the creation of, any lien, security interest, charge or encumbrance upon any of the properties or assets of the Seller under any note, indenture, mortgage, lease agreement, or other agreement, contract or instrument to which the Seller is a party or by which the Seller’s property is bound or affected.

B. Title to the Securities. The Seller has record and beneficial ownership of the Purchased Securities. The Seller has good and valid title to the Purchased Securities, free and clear of all liens, claims, encumbrances and similar restrictions. The Seller has the absolute legal right, power and authority to sell to the Purchasers the Purchased Securities to be sold by the Seller, and upon transfer to the Seller of the Purchase Price, the Seller will pass to the Purchasers good and valid title to the Purchased Securities, free and clear of all liens, claims, encumbrances and similar restrictions.

C. Brokers and Finders. No Person acting on behalf or under the authority of the Seller is or will be entitled to any broker’s, finder’s, or similar fee or commission in connection with the transactions contemplated hereby.

D. Acknowledgements. The Seller acknowledges and agrees as follows:

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Section 5. Representations, Warranties and Acknowledgements of the each of the Purchasers.

Each Purchaser, solely in respect of itself, represents and warrants to the Seller as follows:

A. Investment Representations.

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B. Brokers and Finders. No Person acting on behalf or under the authority of such Purchaser is or will be entitled to any broker’s, finder’s, or similar fee or commission in connection with the transactions contemplated hereby.

C. Acknowledgements. Each Purchaser acknowledges and agrees as follows:

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Section 6. Successors and Assigns.

This Agreement shall bind and inure to the benefit of the parties and their respective successors, assigns, administrative agents, heirs and estate, as the case may be. No party may assign its rights and obligations under this Agreement to any third party without the prior consent of the other parties hereto.

Section 7. Entire Agreement.

This Agreement and the other writings and agreements referred to herein or delivered pursuant hereto contain the entire agreement between the parties with respect to the subject matter hereof and supersede all prior arrangements or understandings between such parties with respect thereto. This Agreement shall become effective and be in full force and effect, immediately upon execution and delivery of this Agreement by all parties hereto.

Section 8. Amendments.

The terms and provisions of this Agreement may not be modified or amended, or any of the provisions hereof waived, temporarily or permanently, except pursuant to the written consent of the parties hereto.

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Section 9. Counterparts.

This Agreement may be executed in any number of counterparts, each of which shall be deemed to be an original instrument, but all of which together shall constitute one instrument.

Section 10. Governing Law.

This Agreement shall be governed by and construed in accordance with the laws of the State of Florida without regard to principles of conflicts of laws.

[Signature pages to follow]

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IN WITNESS WHEREOF, the parties hereto have caused this Securities Purchase Agreement to be executed as of the date first written above.

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