The show was originally titled These Friends of Mine for its first season, but the name was changed to Ellen to avoid confusion with the NBC series Friends, which premiered in September 1994.

Between the first and second seasons, two main characters disappeared from the show without any on-screen explanation.

The theme song used from season three onward is a version of "So Called Friend" by the Scottish band Texas, performed with altered lyrics; the band itself later appeared in one of the show's opening sequences.

During the third and fourth seasons, the show ran a recurring gag in which nearly every episode had a completely different opening credits sequence, often featuring singing, dancing, and celebrity guest stars, framed as Ellen's ongoing search for the perfect opening.

In the episode "The Puppy Episode," the coming-out scene was staged as a gag: Ellen turns to tell Laura Dern's character "I'm gay!" only to realize she has spoken directly into an airport public address microphone, announcing it to the entire terminal.

Ellen DeGeneres's real-life mother Betty DeGeneres appeared in a cameo during "The Puppy Episode," briefly seen among the shocked airport onlookers, and also appeared in another episode, "Makin' Whoopie."

"The Puppy Episode" featured a large number of high-profile guest stars including Oprah Winfrey, Laura Dern, Demi Moore, Billy Bob Thornton, k.d. lang, Melissa Etheridge, Gina Gershon, Dwight Yoakam, and Jorja Fox.

Ellen DeGeneres came out as gay in real life concurrently with the airing of "The Puppy Episode," revealing it on The Oprah Winfrey Show and in Time magazine around the same time her character came out on the series.

The coming-out storyline sparked major controversy, leading ABC to place a parental advisory warning at the start of every episode, and after an initial ratings boost the show's viewership declined amid backlash over its 'gay content,' contributing to its cancellation in May 1998.

Emma Thompson won a Primetime Emmy Award for Outstanding Guest Actress in a Comedy Series for her guest appearance in the episode "Emma."