Exhibit 32.1

CERTIFICATION OF PRINCIPAL EXECUTIVE OFFICER

In connection with the Quarterly Report of Ligand Pharmaceuticals Incorporated (the Company) on Form 10-Q, as amended by the
accompanying amendment No. 1 on Form 10-Q/A for the quarter ended September 30, 2015, as filed with the Securities and Exchange Commission on the date hereof (the Report), I, John L. Higgins, Chief Executive Officer of the
Company, certify, pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002, that to my knowledge:



| | (1) | The Report fully complies with the requirements of Section 13(a) or Section 15(d), as applicable, of the Securities Exchange Act of 1934, as amended; and
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| | (2) | The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.
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|Date: |  | December 23, 2015 |  | /s/ John L. Higgins                                                  
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|      |  |                   |  |                                                                      
|      |  |                  
|      |  |                   |  | John L. Higgins
Chief Executive Officer
(Principal Executive Officer)

The foregoing certification is being furnished solely to accompany the Report pursuant to 18 U.S.C.
Section 1350, and is not being filed for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, and is not to be incorporated by reference into any filing of the Company, whether made before or after the date hereof,
regardless of any general incorporation language in such filing. A signed original of this written statement required by Section 906 has been provided to the Company and will be retained by the Company and furnished to the Securities and
Exchange Commission or its staff upon request.

CERTIFICATION OF PRINCIPAL FINANCIAL OFFICER

In connection with the Quarterly Report of Ligand Pharmaceuticals Incorporated (the Company) on Form 10-Q, as amended by the
accompanying amendment No. 1 on Form 10-Q/A for the quarter ended September 30, 2015, as filed with the Securities and Exchange Commission on the date hereof (the Report), I, Matthew Korenberg, Vice President, Finance and Chief
Financial Officer of the Company, certify, pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002, that to my knowledge:



| | (1) | The Report fully complies with the requirements of Section 13(a) or Section 15(d), as applicable, of the Securities Exchange Act of 1934, as amended; and
| | --- | ---------------------------------------------------------------------------------------------------------------------------------------------------------



---

| | (2) | The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.
| | --- | ----------------------------------------------------------------------------------------------------------------------------------------------------



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|Date: |  | December 23, 2015 |  | /s/ Matthew Korenberg                                                                              
|      |  |                  
|      |  |                   |  |                                                                                                    
|      |  |                   |  | Matthew Korenberg
Vice President, Finance and Chief
Financial Officer (Principal
Financial Officer)

The foregoing certification is being furnished solely to accompany the Report pursuant to 18 U.S.C. Section 1350, and is
not being filed for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, and is not to be incorporated by reference into any filing of the Company, whether made before or after the date hereof, regardless of any general
incorporation language in such filing. A signed original of this written statement required by Section 906 has been provided to the Company and will be retained by the Company and furnished to the Securities and Exchange Commission or its staff
upon request.