Glover’s father is of English, Czech, and Swedish descent, while his mother has Czech (area surrounding Milevsko) and German ancestry. As a child, Glover attended the Mirman School from first grade through ninth grade. He then attended both Venice High for tenth and eleventh grade, and Beverly Hills High School for twelfth grade; he graduated in 1982.

His breakout role was as George McFly in Robert Zemeckis’s Back to the Future, an international box office success in 1985; his character was the father of Marty McFly, despite being three years younger than Michael J. Fox in real life. Glover and the producers could not agree on suitable terms for him to appear in the sequels, so the role was greatly reduced and recast. In Back to the Future Part II, Zemeckis reused brief footage of Glover which had been filmed for the first film. Glover was billed as “George McFly in footage from Back to the Future” in the closing credits. The older footage was combined with new footage of actor Jeffrey Weissman wearing a false chin, nose and cheekbones, and various obfuscating methods – in the background, wearing sunglasses, rear shot, upside down – to play George McFly. Because these methods suggested that Glover himself had performed for the film, he sued the producers on the grounds that they had used his likeness without permission, as well as not having paid him for the reuse of the footage from the original film. As a result of this suit, there are now clauses in the Screen Actors Guild collective bargaining agreements which state that producers and actors are not allowed to use such methods to reproduce the likeness of other actors.

Glover appeared on Late Night with David Letterman on July 28, 1987 to promote River’s Edge. Unknown to Letterman and the audience, Glover appeared in character as Rubin from the then-unreleased film Rubin and Ed, wearing platform shoes and a wig. Rather than a conventional interview, Glover staged an Andy Kaufman-like prank. After being goaded by a woman in the audience (who some argue had been planted), Glover stated he “knew that this was gonna happen” and “the press, they can do things, they can twist things around.” After challenging Letterman to an arm-wrestling match, Glover delivered an impromptu karate kick a few feet from Letterman while stating “I’m strong…I can kick!” Letterman then abruptly ended the segment by walking off stage, saying “I’m going to check on the Top 10,” as the program cut to commercial.

In 1989, during a hiatus from films, Glover released an album titled The Big Problem Does Not Equal the Solution, The Solution Equals Let It Be through Restless Records, produced by Barnes & Barnes. The album features original songs such as “Clowny Clown Clown”, odd versions of Lee Hazlewood’s “These Boots Are Made for Walkin'”, and Charles Manson’s “I’ll Never Say Never to Always” (sung in falsetto), and readings from his art books Rat Catching and Oak Mot. Sample pages from these books are featured in the album’s liner notes.

He has continued to play exceedingly eccentric types, including playing Andy Warhol in Oliver Stone’s The Doors in 1991, as well as the title characters in Bartleby (2001) and Willard (2003). He received mainstream attention as the “Thin Man” in the Charlie’s Angels films; the character had initially been cast as a speaking role, but Glover, noting that the lines as written were exposition, convinced the producers to eliminate the lines to create a precise image for the character.

Glover appeared in the 2007 film Beowulf as the monster Grendel, playing the part through performance capture technology. The film was Glover’s first collaboration with director Robert Zemeckis since the original Back to the Future film. He voiced the character “6” in the film 9. Glover played Ilosovic Stayne / The Knave of Hearts in Tim Burton’s Alice in Wonderland. He played the one-armed bellman in Hot Tub Time Machine, and the unwitting employee of Robert De Niro’s character in The Bag Man.

The subsequent confusion and controversy surrounding his appearance was compounded by the fact that Rubin and Ed was not released until 1991. However, the film had been in development since before Back to the Future, and Glover already had devised Rubin’s “look” by 1985. Glover has refused to go into detail about the reasons for his behavior on the show, other than to mention that he was flattered that fans are still speculating on the performance decades later. He also stated that he prefers there to be an “air of mystery” about the appearance. In an interview in 2011, Back to the Future co-star Michael J. Fox talked about the incident with Letterman, saying “Crispin isn’t crazy, just excitable.”

Glover was recognized for his directorial work in 2013 when the Museum of Arts and Design in New York City staged the series It Is Crispin Hellion Glover. The program consisted of screenings of all of his directorial work, live performances, and speaking engagements.