Mulroney played the main antagonist Francis Gibson in NBC's Crisis (2014), Dr. Walter Wallace in Pure Genius (2016–2017), Sean Pierce in Showtime's Shameless (2015–2017), and Bobby Sheridan in USA's The Purge (2018–2019).

[3] Beginning at age 18, Mulroney studied communications at Northwestern University in Evanston, Illinois,[5] where he was a member of the Phi Gamma Delta fraternity, and graduated in 1985.

"[7] In his senior year in college, Mulroney responded to a sign-up sheet and auditioned in front of WMA agent Barbara Gale,[3] who offered him a contract and asked him to relocate to Hollywood.

[8] In his first decade acting, Mulroney appeared in a slew of drama films often dealing with heavy subject matter: Sin of Innocence (1986), in which he played a stepbrother romantically involved with his stepsister after their parents marry; Daddy (1987), in which he played the boyfriend in a couple struggling with teenage parenthood; the Lee Grant sibling family drama Staying Together (1989); Unconquered (1989), in which he portrayed the son of Richmond Flowers Sr., an opponent of Alabama Governor George Wallace's segregationist policies; Longtime Companion (1989), in which he portrayed the first HIV/AIDS patient to die of the disease in a widely released film; Where the Day Takes You (1992), in which he plays the leader of a group of teenage runaways trying to survive in the streets of Los Angeles; and supporting roles in the Emmy Award-nominated Family Pictures (1993), which dealt with the struggles of raising a child with autism, and Bastard out of Carolina (1996), which dealt with abuse and molestation.

In 1988, Mulroney appeared in the baseball flick Long Gone, for which he was nominated for Best Supporting Actor in a Miniseries or Movie at the CableACE Awards.

While filming, in 1986,[3] Keener was caught in a river current and floated precariously close to whitewater rapids when Mulroney jumped in and the pair were picked up half a mile downstream.

Mulroney appeared in a number of western films throughout this period, namely Young Guns in 1988, Silent Tongue and The Last Outlaw in 1993, and Bad Girls in 1994.

[10] The Sam Shepard-directed Silent Tongue would mark the second in a series of four collaborations, with the two previously appearing together on screen in Bright Angel (1990), for which Mulroney won the Jury Special Prize at the Torino International Festival of Young Cinema.

[5] Mulroney appeared in the thriller films Point of No Return in 1993; Copycat in 1995; the Palme d'Or-nominated Kansas City, and The Trigger Effect in 1996.

Mulroney has appeared in many films, including as the male lead in My Best Friend's Wedding alongside Julia Roberts and Cameron Diaz.

In 2005, he played a male escort alongside Debra Messing in The Wedding Date, and co-starred in the ensemble film The Family Stone, with Sarah Jessica Parker.

This would mark Mulroney's last on-screen appearance on television for a number of years, later revealing in a May 2007 interview that he had turned down TV series roles in favor of film.