[4] O'Neill began his public service as a computer systems analyst with the United States Department of Veterans Affairs, where he served from 1961 to 1966.

[5] O'Neill along with Kenneth W. Dam and William A. Morrill resisted President Richard Nixon in 1973 when he tried cutting off federal funding to the Massachusetts Institute of Technology in retaliation for it allowing anti-war protests over the Vietnam War.

[6] According to Frank Zarb, he, O'Neill, Roy Ash and Fred Malek mostly ran the government in 1974 as Nixon's authority was eroded with the Watergate scandal.

[13] In 2005, he established a consulting firm named Value Capture that advises health care institutions on reducing expenses as well as increasing safety of patients.

Bush then pursued and convinced O'Neill to chair an advisory group on education that included Lamar Alexander, Bill Brock, and Richard Riley.

[14] In December 1997, O'Neill together with Karen Wolk Feinstein, President of the Jewish Healthcare Foundation, founded the Pittsburgh Regional Health Initiative (PRHI).

[20] In 2006, he published the results of a study conducted from 2003 to 2005 at Allegheny General Hospital along with a team of doctors led by Richard Shannon, in the Joint Commission Journal on Quality and Patient Safety.

During his tenure he often disagreed with UPMC's CEO Jeffrey Romoff and also opposed its plans to shut Highmark-insured patients out of receiving treatment at affiliated hospitals in 2019.

[23] O'Neill also helped Turkey, Argentina and Brazil in receiving loans from the International Monetary Fund but opposed more financial assistance.

His cavalcade was once attacked with eggs during a visit to Argentina because of his stating the country had “no industry to speak of.” He however also encouraged governments to increase grants by the World Bank and cracking down on monetary support of terrorism.

O'Neill claims that Bush appeared somewhat unquestioning and incurious, and that the Iraq War was planned from the first National Security Council meeting, soon after the administration took office.

[29] In an October 16, 2007, opinion piece published in The New York Times, he wrote of the reluctance among politicians to address comprehensive reform in the U.S. health care system.

In the opinion, he suggested that doctors and hospitals should be required to report medical errors within 24 hours, as well as moving malpractice suits out of the civil courts and into a new, independent body.

[30] In April 2016, he was one of eight former Treasury secretaries who called on the United Kingdom to remain a member of the European Union ahead of the June 2016 Referendum.