His best known roles include Perry Cox in Scrubs, Bob Slydell in Office Space, Captain Hendrix in The Rock, Sergeant Red O'Neill in Oliver Stone's Platoon, Marv in Stone's Wall Street, FBI agent Ben Harp in Point Break, and the serial killer Edgler Foreman Vess in the TV miniseries of Intensity, based on the novel by Dean Koontz.

[3] Upon completing his education, McGinley did a variety of different work, including off-Broadway and Broadway productions, and a two-year stint on the soap opera Another World.

[5] He worked continually throughout the 1990s, appearing in films such as Point Break (1991), Highlander II: The Quickening (1991), Article 99 (1992), Wagons East (1994), Seven (1995), The Rock (1996), Set It Off (1996), Nothing to Lose (1997) and Office Space (1999) (McGinley improvised several takes about his character's fondness for Michael Bolton).

McGinley has done voice-over work on animated television series, including the superhero The Atom on several episodes of Justice League Unlimited, a guest appearance as "The White Shadow", the secret government agent overseeing Huey Freeman on The Boondocks, voicing The Whammer on the PBS Kids Go!

McGinley received critical acclaim for his performance as a serial killer in Dean Koontz's suspense drama Intensity (1997).

McGinley has said that there are three things over the course of the series that he improvises: his constant usage of girls' names for JD, which he does with all his real friends; his whistle, which he describes as "a bad habit"; and his habit of touching his nose, a tribute to Robert Redford's character in The Sting, and which he says means "It's gonna be OK."[6] Since the NFL season of 2007, McGinley has played the "Commish" of the More Taste League commercials for Miller Lite.

[9] In 2012, it was announced that McGinley would be a recurring character on USA Network's Burn Notice as Michael Westen's original CIA trainer, Tom Card.

In the same year, he appeared in a State Farm insurance commercial as a father wanting his college graduate son to move out.

McGinley played a crusty retired sheriff who reluctantly helps his perky replacement fight the demons that have taken over their small town.

[15] McGinley owns a stake in one of Billy Gilroy's New York SoHo bistros, along with fellow actor Willem Dafoe.

McGinley is a vocal supporter for the disabled community, and commented in late 2011 on the experience of raising a teenager with Down syndrome along with two young daughters: [Billie's] biggest strength is language.

He maintains a home in Malibu, California, and is well known as a member of the "Malibu Mob",[18] a group of celebrity friends and neighbors including John Cusack, Tony Danza, former Detroit Red Wings defenseman Chris Chelios, big-wave surfer Laird Hamilton, beach volleyball pro Gabrielle Reece, and tennis player John McEnroe.

John said his brother Mark felt his desk shake after the North Tower was hit, which prompted him to get up and exit the building.