Diamond's most memorable role was that of the nerdy Samuel “Screech” Powers on the television show Saved by the Bell, a role he played for close to thirteen years from its beginning as Good Morning, Miss Bliss (1988–89) through its final incarnation, Saved by the Bell: The New Class (1994–2000).

Continuing the series into college, Saved by the Bell: The College Years shows most of the cast transplanted into not only the same college, but also the same college dormitory, where Screech continued his typical misadventures. The College Years was canceled after one season. Diamond returned to Bayside High as Principal Belding's assistant in The New Class episodes, remaining with the show until its cancellation.

After Saved By The Bell ended, Diamond was featured on a number of game and reality shows including The Weakest Link, Celebrity Boxing 2, and professional wrestling matches. Diamond has also made several cameo appearances in films, including appearances in Dickie Roberts: Former Child Star in 2003 and in Made in 2001.

In 2001, Diamond released the video Dustin Diamond Teaches Chess, in which he shows various techniques for becoming a better chess player. It is punctuated by appearances by Diamond, in various costumes, such as dressing as Screech, Liberace and Al Jolson-style black face.

In 2009, he also acted out a small part, that of “Alumnus Guy #1,” in American Pie Presents: The Book of Love.

In 2010, he acted in a supporting role in the sports comedy “Tetherball: The Movie.” In it Dustin plays the “Foul Mouth's” down-on-his luck coach.