From 1980 through 2000, he supported Republican presidential candidates in the United States, with the exception of Bill Clinton, who he supported during his first election campaign in 1992. In 2004, however, he supported the presidential campaign of John Kerry, a Democrat, angered by George W. Bush's support of the Federal Marriage Amendment designed to enshrine in the Constitution marriage as a union between a man and a woman, as well as what he saw as his administration's incompetence over its Iraq War management.

Sullivan was born in South Godstone, Surrey, into a Roman Catholic family of Irish descent, and was brought up in the nearby town of East Grinstead, West Sussex. He was educated at Reigate Grammar School and Magdalen College, Oxford, where he was awarded a first-class Bachelor of Arts in modern history and modern languages. In his second year, he was elected President of the Oxford Union for Trinity term 1983.

One of the most important intellectual and political influences on Sullivan is Michael Oakeshott. Sullivan describes Oakeshott's thought as "an anti-ideology, a nonprogramme, a way of looking at the world whose most perfect expression might be called inactivism." He argues "that Oakeshott requires us to systematically discard programmes and ideologies and view each new situation sui generis. Change should only ever be incremental and evolutionary. Oakeshott viewed society as resembling language: it is learned gradually and without us really realising it, and it evolves unconsciously, and for ever." In 1984, he wrote that Oakeshott offered "a conservatism which ends by affirming a radical liberalism." This "anti-ideology" is perhaps the source of accusations that Sullivan "flip-flops" or changes his opinions to suit the whims of the moment. He has written, "A true conservative—who is, above all, an anti-ideologue—will often be attacked for alleged inconsistency, for changing positions, for promising change but not a radical break with the past, for pursuing two objectives—like liberty and authority, or change and continuity—that seem to all ideologues as completely contradictory."

In 1986, Sullivan began his career with The New Republic magazine, serving as its Editor from 1991 to 1996. In that position, he expanded the magazine from its traditional roots in political coverage to cultural issues and the politics surrounding them. During this time, the magazine generated several high-profile controversies.

While completing graduate work at Harvard in 1988, Sullivan published an attack in Spy magazine on Rhodes Scholars, "All Rhodes Lead Nowhere in Particular," which dismissed recipients of the scholarship as "hustling apple-polisher[s]"; "high-profile losers"; "the very best of the second-rate"; and "misfits by the very virtue of their bland, eugenic perfection." "[T]he sad truth is that as a rule," Sullivan wrote, "Rhodies possess none of the charms of the aristocracy and all of the debilities: fecklessness, excessive concern that peasants be aware of their achievement, and a certain hemophilia of character." Author Thomas Schaeper notes that "[i]ronically, Sullivan had first gone to the United States on a Harkness Fellowship, one of many scholarships spawned in emulation of the Rhodes program."

Sullivan, like Marshall Kirk, Hunter Madsen, and Bruce Bawer, has been described by Urvashi Vaid as a proponent of "legitimation", seeing the objective of the gay rights movement as being "mainstreaming gay and lesbian people" rather than "radical social change". Sullivan wrote the first major article in the United States advocating for gay people to be given the right to marry, published in The New Republic in 1989. Many gay rights organisations attacked him for the stance at the time. Many on "the gay left" believed that he was promoting "assimilation" into "straight culture", when the aim of most at that time was to alter codes of sexuality and society as a whole, rather than fitting gays into it. However, his arguments eventually became widely accepted and formed the basis of the modern movement to allow same-sex marriage. In the wake of the United States Supreme Court rulings on same-sex marriage in 2013 (Hollingsworth v. Perry and United States v. Windsor), New York Times op-ed columnist Ross Douthat suggested that Sullivan might be the most influential political Writer of his generation, writing, "No intellectual that I can think of, writing on a fraught and controversial topic, has seen their once-crankish, outlandish-seeming idea become the conventional wisdom so quickly, and be instantantiated so rapidly in law and custom."

In 1994, Sullivan published excerpts on race and intelligence from Richard Herrnstein and Charles Murray's controversial The Bell Curve, which argued that some of the measured difference in IQ scores among racially defined groups was a result of genetic inheritance. Almost the entire editorial staff of the magazine threatened to resign if material that they considered racist was published. To appease them, Sullivan included lengthy rebuttals from 19 Writers and contributors. He has continued to speak approvingly of the research and arguments presented in The Bell Curve, writing, "The book ... still holds up as one of the most insightful and careful of the last decade. The fact of human inequality and the subtle and complex differences between various manifestations of being human—gay, straight, male, female, black, Asian—is a subject worth exploring, period." According to Sullivan, this incident was a turning point in his relationship with the magazine's staff and management, which he conceded was already bad because he "was a lousy manager of people". He left the magazine in 1996.

Sullivan began writing for The New York Times Magazine in 1998, but was fired by Editor Adam Moss in 2002. Jack Shafer wrote in Slate magazine that he had asked Moss in an e-mail to explain this decision, but that his e-mails went unanswered, adding that Sullivan was not fully forthcoming on the subject. Sullivan wrote on his blog that the decision had been made by Times executive Editor Howell Raines, who found Sullivan's presence "uncomfortable", but defended Raines's right to fire him. Sullivan suggested that Raines had done so in response to Sullivan's criticism of the Times on his blog, and said he had expected that his criticisms would eventually anger Raines.

In late 2000, Sullivan began his blog, The Daily Dish. The core principle of the blog has been the style of conservatism he views as traditional. This includes fiscal conservatism, limited government, and classic libertarianism on social issues. Sullivan opposes government involvement with respect to sexual and consensual matters between adults, such as the use of marijuana and prostitution. He believes recognition of same-sex marriage is a civil-rights issue but expressed willingness to promote it on a state-by-state legislative federalism basis, rather than trying to judicially impose the change. Most of Sullivan's disputes with other conservatives have been over social issues and the handling of postwar Iraq.

Sullivan supported the 2003 invasion of Iraq by the United States and was initially hawkish in the war on terror, arguing that weakness would embolden terrorists. He was "one of the most militant" supporters of the Bush administration's counter-terrorism strategy immediately following the September 11 attacks in 2001; in an essay for The Sunday Times, he stated, "The middle part of the country—the great red zone that voted for Bush—is clearly ready for war. The decadent Left in its enclaves on the coasts is not dead—and may well mount what amounts to a fifth column." Eric Alterman wrote in 2002 that Sullivan had "set himself up as a one-man House Un-American Activities Committee" running an "inquisition" to unmask "anti-war Democrats", "basing his argument less on the words these politicians speak than on the thoughts he knows them to be holding in secret".

He expressed concern about the election of Pope Benedict XVI in an article in Time Magazine on 24 April 2005, titled "The Vicar of Orthodoxy". He wrote that Benedict was opposed to the modern world and women's rights, and considered gays and lesbians innately disposed to evil. Sullivan has, however, agreed with Benedict's assertion that reason is an integral element of faith.

On the edition of 27 October 2006 of Real Time with Bill Maher, he described conservatives and Republicans who refused to admit they had been wrong to support the Iraq War as "cowards." On 26 February 2008, he wrote on his blog: "After 9/11, I was clearly blinded by fear of al Qaeda and deluded by the overwhelming military superiority of the US and the ease of democratic transitions in Eastern Europe into thinking we could simply fight our way to victory against Islamist terror. I wasn't alone. But I was surely wrong." His Reversal on the Iraq issue and his increasing attacks on the Bush administration caused a severe backlash from many hawkish conservatives, who accused him of not being a "real" conservative.

In February 2007, Sullivan moved his blog from Time to The Atlantic Monthly, where he had accepted an editorial post. His presence was estimated to have contributed as much as 30% of the subsequent traffic increase for The Atlantic's website.

Sullivan endorsed Senator Barack Obama for the Democratic nomination in the 2008 United States presidential election, and Representative Ron Paul for the Republican nomination. He eventually endorsed Obama for President, largely because he believed that he would restore "the rule of law and Constitutional balance"; he also argued that Obama represented a more realistic prospect for "bringing America back to fiscal reason", and expressed a hope that Obama would be able to "get us past the culture war." Sullivan has continued to maintain that Obama is the best choice for President from a conservative point of view. During the 2012 election campaign, he wrote, "Against a radical right, reckless, populist insurgency, Obama is the conservative option, dealing with emergent problems with pragmatic calm and modest innovation. He seeks as a good Oakeshottian would to reform the country's policies in order to regain the country's past virtues. What could possibly be more conservative than that?"

In 2009, The Daily Dish won the 2008 Weblog Award for Best Blog.

In February 2010, Leon Wieseltier suggested in The New Republic that Sullivan, a former friend and colleague, had a "venomous hostility toward Israel and Jews" and was "either a bigot, or just moronically insensitive" toward the Jewish people. Sullivan rejected the accusation and was defended by some Writers, while others at least partly supported Wieseltier.

Sullivan left The Atlantic to begin blogging at The Daily Beast in April 2011. In 2013, he announced that he was leaving The Daily Beast to launch The Dish as a stand-alone website, charging subscribers $20 a year.

Sullivan describes himself as a conservative and is the author of The Conservative Soul. He has supported a number of traditional libertarian positions, favouring limited government and opposing interventionist measures such as affirmative action. However, on a number of controversial public issues, including same-sex marriage, social security, progressive taxation, anti-discrimination laws, the Affordable Care Act, the United States government's use of torture, and capital punishment, he has taken positions not typically shared by conservatives in the United States. In July 2012, Sullivan said that "the catastrophe of the Bush-Cheney years ... all but exploded the logic of neoconservatism and its domestic partner-in-crime, supply-side economics."

Later, Sullivan criticised the Bush administration for its prosecution of the war, especially regarding the numbers of troops, protection of munitions, and treatment of prisoners, including the use of torture against detainees in United States custody. Though he argues that enemy combatants in the war on terror should not be given status as prisoners of war because "terrorists are not soldiers", he believes that the US government must abide by the rules of war—in particular, Article 3 of the Geneva Conventions—when dealing with such detainees. In retrospect, Sullivan said that the torture and abuse of prisoners at the Abu Ghraib prison in Iraq had jolted him back to "sanity". Of his early support for the invasion of Iraq, he said, "I was terribly wrong. In the shock and trauma of 9/11, I forgot the principles of scepticism and doubt towards utopian schemes that I had learned."

In a note posted on The Dish on 28 January 2015, Sullivan announced his decision to retire from blogging. He posted his final blog entry on 6 February 2015. On 26 June 2015, he posted an additional piece in reaction to Obergefell v. Hodges, which legalized same-sex marriage in the United States.