Buckley was born in New York City. He is the son of Aloise Josephine Antonia (née Steiner) and Lawyer and businessman william Frank Buckley, Sr. He is the older brother of the late conservative Writer william F. Buckley, Jr. and the uncle of Christopher Taylor Buckley. He is also the uncle of Brent Bozell III and political consultant william F. B. O'Reilly. His mother, from New Orleans, was of Swiss-German, German, and Irish descent, while his paternal grandparents, from Hamilton, Ontario, Canada, were of Irish ancestry. Graduating from Yale University in 1943 with a Bachelor of Arts degree, where he was a member of Skull and Bones, Buckley enlisted in the United States Navy in 1942 and was discharged with the rank of lieutenant in 1946. After receiving his Bachelor of Laws from Yale Law School in 1949, he was admitted to the Connecticut bar in 1950 and practiced law until 1953, when he joined Catawba as vice President and Director.

In 1968 Buckley challenged liberal Republican U.S. Senator Jacob K. Javits for re-election. Javits won easily, but Buckley received a large number of votes from disaffected conservative Republicans. The New York Times called Buckley's 1968 Senatorial campaign "lonely and unsuccessful." In 1970, he ran on the Conservative Party line for the U.S. Senate, facing the Republican incumbent, Charles Goodell; and the Democratic nominee, Richard Ottinger. Goodell, who had been appointed to the Senate by Governor Nelson Rockefeller following the assassination of Senator Robert F. Kennedy, had moved left, especially as an opponent of the Vietnam War. Buckley's campaign slogan, plastered on billboards statewide, was "Isn't it time we had a Senator?"

In the 1970 election he was elected to the U.S. Senate as the nominee of the Conservative Party of New York, winning 38.7 percent of the vote in a six-candidate race, and served from 1971 until 1977. To date he has been the only candidate of his party, and the last third party registrant, to be successfully nominated and elected to the U.S. Congress.

With Goodell and Ottinger splitting the liberal vote, Buckley won with 39% of the vote and entered the U.S. Senate in January 1971. "He performed well in New York City itself, at a time when the city still had a beating conservative heart in the middle-class neighborhoods of the outer boroughs." Although Buckley had been elected from the Conservative party, it was observed that he'd probably usually vote with the Republicans.

In the spring of 1974, with the Watergate scandal continuing to grow in magnitude and seriousness, Buckley surprised—and in some cases, angered—some of his allies among Republicans when he called upon the increasingly embattled Richard M. Nixon to voluntarily resign the presidency. Buckley said that in doing so, he was making no judgment as to Nixon's technical legal guilt or innocence of the accusations made against him - and he in fact denounced those "in and out of the media who have been exploiting the Watergate affair so recklessly" in what he called an effort "to subvert the decisive mandate of the 1972 election." However, he said that the burgeoning scandal might result in an impeachment process that would tear the country even further apart, so he declared: "There is one way and one way only by which the crisis can be resolved, and the country pulled out of the Watergate swamp. I propose an extraordinary act of statesmanship and courage—an act at once noble and heartbreaking; at once serving the greater interests of the nation, the institution of the Presidency, and the stated goals for which he so successfully campaigned"—Nixon's resignation. Buckley was the first major conservative Republican figure to call for such a resignation. Nixon did not resign at that time, but eventually did lose the support of other key Republican figures, including Sen. Barry Goldwater, and ultimately resigned on Aug. 9, 1974.

During the 1976 Republican National Convention, then-Senator Jesse Helms encouraged a "Draft Buckley" movement, as an effort to stop the nomination of Ronald Reagan for President. Reagan had announced that Pennsylvania Senator Richard Schweiker would be his running-mate if picked; Helms believed that Schweiker was too liberal. The "Draft Buckley" movement was mooted when President Gerald Ford very narrowly won the party's nomination on the first ballot.

After his loss, Buckley moved to Connecticut, and in 1980 received the Republican nomination for the Senate seat being vacated by the retirement of Abraham Ribicoff. He lost the general election to Christopher Dodd, who would go on to hold the seat until his retirement in 2011.

In the first Reagan administration, Buckley served as an undersecretary of State, and then as President of Radio Free Europe/Radio Liberty from 1982 to 1985.

Buckley was nominated by President Ronald Reagan on October 16, 1985, to a seat on the United States Court of Appeals for the District of Columbia Circuit vacated by Judge Edward Allen Tamm. He was confirmed by the United States Senate on December 17, 1985, and received commission on December 17, 1985. He assumed senior status on August 31, 1996. He is currently in inactive senior status and does not maintain chambers or perform judicial duties.

Buckley is the author of four books. Freedom at Risk: Reflections on Politics, Liberty, and the State, was released in December 2010. Buckley discussed Freedom at Risk on C-SPAN on January 12, 2011. His latest book "Saving Congress from Itself" (released December 2014) was sent to every member of the US Senate (114th Congress) by Dallas businessman and Buckley family devotee Chris M. Lantrip.

Buckley went on to a serve as an undersecretary of state—during Reagan’s first term—and a federal appellate judge. In between, Buckley held a number of other positions, including President of Radio Free Europe in the mid-1980s.