DeGeneres briefly attended the University of New Orleans, where she majored in communications. Dissatisfied with university life, she left to work in a law firm and later held a string of jobs, including waitress, bartender, house painter, and oyster shucker. After putting together a comedy routine for a group of friends, DeGeneres was asked to perform in local coffeehouses in the late 1970s. She was soon traveling through the United States on the comedy-club circuit, earning applause with her quirky, naive stories that were punctuated with her loose-limbed gestures. Her style was compared to those of Mary Tyler Moore and Lucille Ball (Ball, Lucille). DeGeneres's act also caught the attention of Showtime, and the cable network named her Funniest Person of the Year in 1982. Her career hit a high note in 1986 after she was invited to perform on The Tonight Show Starring Johnny Carson. Following her humorous rendition of “Phone Call to God,” Carson motioned DeGeneres to sit and chat—the first time a female comedian had been given that honour.

Besides appearing on television in stand-up comedy routines, DeGeneres had parts in such television shows as One Night Stand (1989), Open House (1989–90), and Laurie Hill (1992). In 1994 she starred in These Friends of Mine; its name changed to Ellen the following season. The show was a success, earning nominations for Golden Globe, American Comedy, and Emmy awards. In 1997 DeGeneres revealed that she was gay, and Ellen became the first prime-time show to feature an openly gay lead character. After the show ended in 1998, DeGeneres eventually moved to the daytime arena, launching her own syndicated talk show, The Ellen DeGeneres Show, in 2003. The show earned more than 20 daytime Emmy Awards in its first five seasons.

In addition to her television work, DeGeneres appeared in such films as Coneheads (1993), Mr. Wrong (1996), and the animated feature film, Finding Nemo (2003), in which she provided the voice of the forgetful but lovable Dory. She also hosted a number of awards shows, most notably the Academy Awards (Academy Award) in 2007. Her comedic essays were collected in the bestselling books My Point…and I Do Have One (1995) and The Funny Thing Is … (2003).