Lloyd's first major motion picture role was as a psychiatric patient in One Flew Over the Cuckoo's Nest. However, he may be most remembered for his roles as Reverend Jim Ignatowski, the ex-hippie cabbie on the TV sitcom Taxi, and the eccentric inventor Emmett "Doc" Brown in the Back to the Future trilogy of movies.
Lloyd also played notable roles as Klingon Commander Kruge in Star Trek III: The Search for Spock, Professor Dimple in an episode of Road to Avonlea, the villain Judge Doom in Who Framed Roger Rabbit and Uncle Fester in The Addams Family.
Lloyd also appeared as the lead character in the computer game Toonstruck. He performs the voice of The Hacker on the children's math mystery cartoon Cyberchase (January 2002-present) on PBS Kids GO!. In 1999, Lloyd starred in the movie It Came From the Sky with Yasmine Bleeth. On one episode of Malcolm in the Middle, he plays Malcolm's paternal grandfather. He portrayed the Constitutionalist Lawrence Lessig (who in real life is twenty-three years younger than Lloyd) in an episode of the sixth season of the West Wing.
Many of Lloyd's roles seem to lean toward comic relief, whether as hyper characters like Reverend Jim or Doc Brown, or as uptight conservatives such as in The Dream Team and Mr. Mom. Lloyd has showed considerable range as a dramatic actor, however, in movies such as Things to Do in Denver When You're Dead as a leprous projectionist, and Wit.
Lloyd rarely appears in public or gives interviews (he gave a rare interview on Channel 4's 100 Greatest Family Films in 2005). Some of his best friends, co-stars and fans who meet him describe him as a very shy and quiet man.Lloyd's most recent role was on the Fox sitcom Stacked, opposite Pamela Anderson; however, it was cancelled during the second season.