The muscular, 6'5" actor is probably most widely recognized for his work with director David Lynch, however. McGill first worked with Lynch in the 1984 adaptation of Frank Herbert's Dune. McGill later appeared as a major character on the TV series Twin Peaks, in which he played Ed Hurley, a sensitive mechanic torn between his high school sweetheart, Norma Jennings, and his shrewish, one-eyed wife, Nadine. Ed and Norma's troubled romance was one of the show's major storylines. Subsequently, McGill also appeared in Lynch's 1999 film, The Straight Story, again as a mechanic.

In 1991, McGill and his Twin Peaks spouse Wendy Robie appeared as the husband-and-wife villains of the Wes Craven feature, The People Under the Stairs. Also, in 1995 he had a major role in the action film Under Siege 2: Dark Territory.

Babylon 5 producer J. Michael Straczynski originally intended for Everett McGill to play the role of Major Ryan in the episode Severed Dreams. However he did not know McGill's first name, so when he asked to have McGill contacted Straczynski was asked if he meant Bruce McGill, to which he replied yes. Even though it became apparent to Straczynski when Bruce McGill met him for lunch that this wasn't the McGill he had in mind, Straczynski decided to use Bruce McGill instead.

He appeared in My Fellow Americans as "twisted psycho" Colonel Paul Tanner, and in Under Siege 2 as an equally twisted and ruthless mercenary.