[5][6] Kristol played a leading role in the defeat of the Clinton health care plan of 1993,[7] as well as for advocating the 2003 invasion of Iraq.

[15] In 1976, Kristol worked for Daniel Patrick Moynihan's United States Senate campaign, serving as deputy issues director during the Democratic primary.

After teaching political philosophy and U.S. politics at the University of Pennsylvania and Harvard's Kennedy School of Government, Kristol went to work in government in 1985, serving as chief of staff to United States secretary of education William Bennett during the Reagan administration, and later, as chief of staff to the vice president under Dan Quayle in the George H. W. Bush administration.

The New Republic dubbed Kristol "Dan Quayle's brain" when he was appointed the vice president's chief of staff.

In 2003, Kristol and Lawrence F. Kaplan wrote The War Over Iraq: America's Mission and Saddam's Tyranny, in which the authors analyzed the Bush Doctrine and the history of Iraqi-U.S. relations.

[17] After the Republican sweep of both houses of Congress in 1994, Kristol established, along with John Podhoretz, the conservative news magazine The Weekly Standard.

For ten years, Kristol was a regular panelist on Fox News Sunday and often contributed to the nightly program Special Report with Bret Baier.

Notable regular guests including Garry Kasparov, Anne Applebaum, Harvey Mansfield, and Larry Summers have been featured to provide insights into their respective fields and to share their perspectives on a range issues.

In the first of what would become many strategy memos written for Republican policymakers, Kristol said the party should "kill", not amend, President Clinton's health care plan.

A later memorandum used the phrase "There is no health care crisis", which Senate Minority Leader Bob Dole used in his response to Clinton's 1994 State of the Union address.

In 1998, he joined other foreign policy analysts in sending a letter to President Clinton urging a stronger posture against Iraq.

[33][34] Kristol argued that Saddam Hussein posed a grave threat to the United States and its allies: "The only acceptable strategy is one that eliminates the possibility that Iraq will be able to use or threaten to use weapons of mass destruction.

"[35] In 1998 he and Robert Kagan wrote a New York Times piece where they said "bombing Iraq isn't enough" and called on Clinton to invade the country.

"[37] After the Bush administration developed its response to the September 11, 2001 attacks, Kristol said: "We've just been present at a very unusual moment, the creation of a new American foreign policy.

He also wrote an op-ed strongly criticizing United States secretary of defense Donald Rumsfeld, saying he "breezily dodged responsibility" for planning mistakes made in the Iraq War, including insufficient troop levels.

[39] In September 2006, he and fellow commentator Rich Lowry wrote, "There is no mystery as to what can make the crucial difference in the battle of Baghdad: American troops.

"[47] In 2010, Kristol criticized the Obama administration and Joint Chiefs of Staff chairman Admiral Mike Mullen for an unserious approach to Iran.

"[48] In the 2010 affair surrounding the disclosure of U.S. diplomatic cables, Kristol spoke strongly against the organization and suggested using "our various assets to harass, snatch, or neutralize Julian Assange and his collaborators, wherever they are.

"[50][51] Kristol backed President Barack Obama's decision to intervene in the Libyan Civil War in 2011 and urged fellow conservatives to support the action.

He stated: "Just filled out my early absentee ballot in VA for Joe Biden & Kamala Harris, Mark Warner, and Jennifer Wexton.

[61] Defending Democracy Together spent hundreds of thousands of dollars in January 2024 to support Nikki Haley and run advertisements against Trump in the 2024 Republican presidential primary, the Washington Examiner reported.

[63] Their daughter, Anne, is married to writer Matthew Continetti, editor-in-chief of The Washington Free Beacon website.