While teaching at Corpus Christi in 1958, Bob Denver shot the pilot for the TV series The Many Loves of Dobie Gillis, and left teaching for his first professional acting job as a regular on the series when it was picked up in 1959. From 1959 to 1963, Denver appeared on Dobie Gillis as Maynard G. Krebs, the teenaged beatnik best friend of Dobie Gillis, played by Dwayne Hickman. While he was on Dobie Gillis, Denver also appeared on the NBC interview program, Here’s Hollywood. Denver’s first feature film appearance was in the service farce, A Private’s Affair, with Sal Mineo in 1959. He landed a small role in the 1963 Jimmy Stewart film, Take Her, She’s Mine, playing a beatnik poet working at a coffee shop. He was credited as Robert Denver. Denver also appeared in the 1964 beach film For Those Who Think Young with Tina Louise prior to the development of Gilligan’s Island. He also had a one-time role replacing the actor who played Dudley A. “Dud” Wash, the husband of Charlene Darling of The Darlings, on The Andy Griffith Show which was aired March 30, 1964 (he appeared in only one episode). This was done by the network to promote Denver’s face and make him more familiar to the viewing audience, since Gilligan’s Island was about to go on air. Bob Denver is remembered primarily as a comic actor. However, he also appeared in one dramatic role on television, as a physician (Dr. Paul Garrett) in one episode of Dr. Kildare, telecast on October 10, 1963; the episode, “If You Can’t Believe the Truth …”, also featured Barbara Eden and Ken Berry. Denver also played a bit part in one episode of The Silent Service in 1957 (S01 E37: “The Loss of the Tang”).

After Dobie Gillis ended in 1963, Bob Denver landed the title role on the sitcom Gilligan’s Island, which ran for three seasons (1964–67) on CBS, and became a staple of later syndication. His role as the well-meaning, but bumbling, first mate among a small cast of shipwrecked castaways became the one for which he is most remembered. During the run, Denver privately went out of his way to help his costars who warmly appreciated his efforts, such as successfully demanding that Russell Johnson and Dawn Wells be included in the series’ opening credits and insisting that Wells get an equal share of the show’s publicity with Tina Louise. After the conclusion of Gilligan’s Island, Denver appeared in films such as Who’s Minding the Mint? (1967), The Sweet Ride (1968) and Did You Hear the One About the Traveling Saleslady? (1968), opposite Phyllis Diller. He also performed in other TV shows, such as The Good Guys (1968–1970), Love, American Style and Dusty’s Trail (1973) (a facsimile of Gilligan’s Island, with the basis of a lost wagon train headed to California). He also starred as “Junior” in the Sid and Marty Krofft children’s program Far Out Space Nuts (1975). In 1976, The Wackiest Wagon Train in the West was a feature movie created from four episodes of Dusty’s Trail. A decade after CBS left the castaways in limbo, he returned to the role of Gilligan – along with many of his former co-star castaways – lending his voice to the animated The New Adventures of Gilligan series, its sequel Gilligan’s Planet, and the live-action made-for-TV reunion movies Rescue from Gilligan’s Island, The Castaways on Gilligan’s Island and The Harlem Globetrotters on Gilligan’s Island. He also played four separate guest roles on Fantasy Island, on ABC from 1978 to 1980. In 1983, he starred in the television pilot, The Invisible Woman, as the bumbling mad scientist uncle of the title character, a journalist, and in the TV movie High School U.S.A..

In 1970, Bob Denver replaced Woody Allen in the original Broadway production of Allen’s hit comedy Play It Again, Sam, earning praise from New York Times critic Clive Barnes for conveying “a genuine clown-like wistfulness” that Barnes had found lacking in Allen’s own performance in the starring role. Later in his life, Denver returned to his adopted home of Princeton, West Virginia, and became an FM radio personality. He and his wife, Dreama, ran a small “oldies format” radio station, WGAG-LP 93.1 FM. He also earned a small income making public appearances, often costumed as Gilligan. During the 1980s, he re-created the character of Gilligan for numerous cameo appearances, including episodes of ALF, Meego, and Baywatch, as well as a bartender in the 1987 film Back to the Beach. In 1992, he again played Gilligan to benefit the Make-A-Wish Foundation for a West Virginia fundraiser for the organization. Bob Denver died September 2, 2005, at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina. His agent announced that he had died from complications relating to cancer treatment. He was cremated.