He is known for playing the Giant/Fireman in the television series Twin Peaks (1990–1991, 2017), the occasional guest role of Mr. Homn in Star Trek: The Next Generation (1987–1992), and the household butler Lurch in the 1990s Addams Family films.

In 1978, Struycken was discovered as an actor at the corner of Hollywood and Vine in Los Angeles by a woman who had abandoned her car in the middle of the street, calling after him: "We need you for a movie!".

Struycken played Terak in the 1985 TV film Ewoks: The Battle for Endor, a spin-off to the original Star Wars trilogy.

He portrayed the mystical guide-character "The Giant" in David Lynch and Mark Frost's hit 1990–91 ABC television series Twin Peaks.

He appears as the "Moonlight Man" in the 2017 film Gerald's Game and “Grandpa Flick” in Doctor Sleep, the 2019 sequel to Stephen King’s The Shining.

Struycken collaborated on several projects with writer and director Rene Daalder, including the 1986 punk rock musical Population: 1, which featured Tomata du Plenty, of The Screamers, and which was released on DVD in October 2008.