Yasay became a member of the Bar of the state of New York and of the United States Supreme Court. While in New York, he was managing director of the Maceda Philippine News from 1983 to 1987 and senior partner at two law firms—Maceda, Yasay & Tolentino, Esqs., and Yasay & De Castro, Esqs.—from 1979 to 1990. In the Philippines, he was commissioner of San Jose, Yasay & Santos Law Offices from 1987 to 1993.
SEC chairman
In 1993, he was assigned as associate commissioner of SEC. He was chairman from 1995 to 2000.
Yasay was among those who testified in the impeachment trial against President Joseph Estrada on charges of corruption. The probe led to the ouster of Estrada, known as EDSA People Power II in 2001. On February 15, 2010, Yasay apologized to Estrada for "hurting and offending him" but clarified that this was not a retraction of his testimony on the deposed president's "abuse of authority and corruption."
2010 vice presidential bid
On November 29, 2009, he accepted the nomination of the Bangon Pilipinas Party to be its candidate for vice president as the running mate of Jesus is Lord Church founder and president Eddie Villanueva. Among his campaign platform points, Yasay conveyed that the practice of using big-name endorsers should be stopped because it makes the elections a matter of money and popularity. He also said that the voters will only base their votes via the endorsers of the candidate, and that the biggest setback in the fight against corruption was the quick pardon of Joseph Estrada. Yasay lost to Makati City Mayor Jejomar Binay in the vice-presidential elections.
Secretary of Foreign Affairs
He accepted the offer of PresidentRodrigo Duterte to join his Cabinet on May 18, 2016. During his tenure he represented the Duterte administration's policy of an "independent foreign policy" distancing the Philippines from the United States. According to Yasay, the United States had used a "carrot and stick" foreign policy in regard to the Philippines since for their own interest to the detriment of the latter. Yasay was meant by Duterte to serve the post until mid-2017, when Duterte planned to appoint his running mate, Senator Alan Peter Cayetano, as his successor. On March 8, 2017, however, Yasay's appointment was rejected by a unanimous vote of 15–0 by the Commission on Appointments due to questions about his Philippine citizenship status after a period of United States citizenship.
Yasay died on June 12, 2020 in San Juan, Metro Manila due to complications from pneumonia according to his wife. His wife clarified, however, that his pneumonia was a complication from cancer recurrence rather than COVID-19, the latter disease being the cause of a pandemic affecting the world at the time of Yasay's death.