Colomby was born in Brooklyn, New York on September 19, 1952. His father, Harry, is a jazz agent, manager, and school teacher; and his mother, Lee, is a stage Actress. While in grade school, his family moved from Brooklyn to Los Angeles. Colomby attended Beverly Hills High School and graduated in 1970. He attended classes for theatre arts at the Immaculate Heart school, where he enjoyed classic readings and decided to make acting his career.

At age 13, he made his acting debut on the daytime soap opera Days of Our Lives (1965). This led to a succession of guest roles on several television shows, including Room 222 (1972), Ironside (1974), Phyllis (1975), The Streets of San Francisco (1975), Baretta (1976), and Charlie's Angels (1977) among others. Colomby had recurring roles on the sitcom Sons & Daughters in 1974 and the soap opera parody Mary Hartman, Mary Hartman in 1976. He starred on the short-lived comedy Szysznyk with Ned Beatty; and appeared in six episodes of One Day at a Time (1977–78) as Cliff Randall.

The Sports comedy film Caddyshack (1980), was to have Colomby and Michael O'Keefe in the leading roles as rival golf caddies, but when co-stars Chevy Chase, Rodney Dangerfield, Ted Knight, and Bill Murray brought an unexpected life to their characters, the script was gradually retooled to focus more on the adult stars. The finished film had Colomby in a supporting role, and he receives no on-screen credit in the film's opening credits.

Two years later, he played Brian Schwartz in the sex comedy Porky's (1982). Despite negative reviews, the film was a major success, grossing more than $100 million financially. Colomby later returned for the film's two less-successful sequels: Porky's II: The Next Day (1983) and Porky's Revenge! (1985). Colomby has continued to act, but his performances have become less frequent since the 1990s. He is the co-founder of Big Elvin & The Professors' Blues Theater, an acting company that provides a grab bag of music, comedy, street theater and performance art.