Lloyd made his New York theatrical debut in a 1961 production of the play “And They Put Handcuffs on the Flowers” by Fernando Arrabal (1932-). He was reportedly a replacement for another actor. He made his Broadway debut in a 1969 performance of Red, White and Maddox (1969). Until the mid-1970s, Lloyd was primarily a theatrical actor. He performed both on Off-Broadway shows and in Broadway. Lloyd made his film debut in the role of psychiatric patient Max Taber in the drama One Flew Over the Cuckoo’s Nest (1975). His first major role in television was drug-using taxicab driver Jim Ignatowski in the sitcom Taxi (1978). His character was an aging hippie, son of an affluent Boston family , and former student of Harvard University. Ignatowski was one of the sitcom’s most colorful characters and Lloyd won two Primetime Emmy Awards for Outstanding Supporting Actor in a Comedy Series.

In the 1980s and early 1990s, Lloyd played most of his most notable film roles. Lloyd was first nominated for the Saturn Award for Best Supporting Actor, for his role as Dr. Emmett “Doc” Brown in Back to the Future (1985). The award was instead won by rival actor Roddy McDowall (1928-1998). He was nominated for the same award for his role as the evil Judge Doom in Who Framed Roger Rabbit (1988). The award was instead won by rival actor Robert Loggia (1930-2015). Lloyd also performed as a voice actor, voicing the evil sorcerer Merlock in DuckTales the Movie: Treasure of the Lost Lamp (1990) and historical figure Grigori Rasputin (1869-1916) in Anastasia (1997). Lloyd had another notable television role when cast in the role of villain Sebastian Jackal in the sci-fi series Deadly Games (1995). He also played the character Dr. Jordan Kenneth Lloyd, the despised father of the series’ protagonist Dr. Gus Lloyd (played by James Calvert).

Lloyd’s last notable film role in the 1990s was playing the Martian Uncle Martin in My Favorite Martian (1999). The film was an adaptation of the classic sitcom My Favorite Martian (1963), and the character was previously played by Ray Walston (1914-2001). The film under-performed at the box office. In the 2000s, Lloyd played the role of recurring character Cletus Poffenberger in the comic sci-fi series Tremors (2003), and recurring character Professor Harold March in the sitcom Stacked (2005). As March, Lloyd played a retired rocket scientist who was a regular customer of the bookstore which served as the series’ setting. In the 2010s, Lloyd returned to the role of Dr. Emmett “Doc” Brown in cameo appearances in A Million Ways to Die in the West (2014)  and as the protagonist of the short film Back to the Future: Doc Brown Saves the World (2015). By 2020, Lloyd has never retired from acting and continues to appear in various roles.