O’Neill gained stardom for playing a working class father, Al Bundy, on the Fox sitcom Married... with Children (1987–1997) for which he was nominated for the Golden Globe Award for Best Actor – Television Series Musical or Comedy twice.

He had a career resurgence portraying the family patriarch Jay Pritchett on the award-winning ABC sitcom Modern Family (2009–2020), for which he was nominated for three Primetime Emmy Awards for Outstanding Actor in a Comedy Series and won four Screen Actors Guild Awards for Outstanding Ensemble in a Comedy Series.

He has since appeared in the Wayne's World film series (1991–1992), Dutch (1991), Little Giants (1994), Prefontaine (1997), The Spanish Prisoner (1997), The Bone Collector (1999), Sun Dogs (2017), and The Last Shift (2020).

O'Neill worked as a substitute social studies teacher at his alma mater Ursuline High School before becoming an actor.

Richard Eder of The New York Times described the performance as "chilling" adding, "As Paddy Klonski, the brutal young boxer, Edward O'Neill's towering physique, peaceful smile and empty eyes form a genuinely frightening presence".

In 1984, while playing the role of Lennie in a stage production of John Steinbeck's Of Mice and Men at Hartford Stage in Hartford, Connecticut, he was seen by a casting agent from the Fox television network and was asked to audition for the role of Al Bundy[17][18][19] in Married... with Children, a proposed sitcom about a dysfunctional family living in Chicago.

He also made a cameo on the sitcom 8 Simple Rules as the ex-boyfriend of Cate S. Hennessy (played by Katey Sagal, who portrayed O'Neill's wife Peggy Bundy on Married... with Children).

O'Neill went on to appear as Governor Eric Baker, a recurring character on the NBC political drama series The West Wing from 2004 to 2005.

"[28] Gina Bellafante of The New York Times wrote, "Mr. O’Neill exquisitely portrays the straight man to the fire engine of Sofia Vergara".

[29] Barry Garron of The Hollywood Reporter wrote, "O’Neill’s Al Bundy is one of TV’s most unforgettable characters, but this role will let viewers see him in a new light".

Since 2012, O'Neill has done voice-overs in TV advertisements for the over-the-counter form of Zyrtec,[34] along with Walmart's store-branded mobile phone service Straight Talk.

As his voice recording sessions continued and most of his interactions turned out to be with Dory, he began to suspect that Hank was a major character in the film.

[36] Andrew Lawrence of The Guardian gave the show a perfect score declaring, "Forty years of playing cranks on screen has given Ed O’Neill a particular understanding for Sterling’s quirks, gripes and foibles that few others in his field can claim".

[37] Daniel Feinberg of The Hollywood Reporter wrote, "O’Neill leans hard into every aspect of his entitled grotesquerie, from the external — such a bad dye job — to the dazed certainty in his intonations.

[42][43] In the 2012 TV documentary I Am Bruce Lee, O'Neill states that he considers getting his black belt "the greatest achievement of my life, apart from my children.

[45] On November 30, 2023, after the controversial hiring of Republican congressman Bill Johnson as the university's president, O'Neill told Ideastream he was going to return his degree, saying, "I don't want it...