O'Neill started his career in the early 80s appearing in a few films like Ghost Story and Sea of Love. However, it wasn't until the 90s when he gained notoriety in several TV shows. His first TV appearance was in the show H.E.L.P. which also starred Wesley Snipes, among other actors. He followed it with appearances in Picket Fences (with Gregory Itzin), One West Waikiki (with Richard Burgi), The Pretender (with Jon Gries), and NYPD Blue (with Ricky Schroder and Eric Balfour), before landing the role of Richard Walsh on 24.
After his brief appearance on the show, he gained a recurring role on The West Wing as Secret Service Agent Ron Butterfield. He also appeared on four chapters of Boston Public as Dr. Bernard Colbert. He continued with roles on Crossing Jordan (with Ravi Kapoor), LAX (with Frank John Hughes and Nestor Serrano), ER (with Leland Orser and Misha Collins), JAG (with Skye McCole Bartusiak), Commander in Chief (with Harry Lennix, Ever Carradine, Anthony Azizi, and Eyal Podell), and Close to Home (with Michael Rodrick). In 2006, he had another recurring role on The Unit alongside Dennis Haysbert and Ned Bellamy as well as NCIS in recent years, reuniting him with his "West Wing" co-star Mark Harmon. He also had roles on ABC's The Nine, Criminal Minds (with Jayne Atkinson), Women's Murder Club (with John Billingsley, Laura Harris, and Larry Sullivan), Prison Break (with Jude Ciccolella), My Own Worst Enemy (with James Cromwell) and Grey's Anatomy (with Kim Raver). He is appearing the CBS show Extant (with Annie Wersching and Maury Sterling).
O'Neill has also continued to act on many films like The Gun in Betty Lou's Handbag (with Xander Berkeley), Victim of Love: The Shannon Mohr Story (with Gregg Henry and Keith Szarabajka), The Legend of Bagger Vance, Traffic, Secondhand Lions (with Eric Balfour) and American Crime (with Wade Williams). He played a Sector Seven agent in the movie Transformers alongside Jon Voight and Glenn Morshower and appeared in the 2010 film Green Zone with Said Faraj.