- Ellen DeGeneres as Ellen Morgan: Ellen Inez Morgan is the main character of the sitcom. In season one, Ellen works in a Los Angeles bookstore called "Buy the Book." In the second season, she purchases the bookstore from her boss and becomes its owner. Throughout season four, hints were made to her sexuality and near the end of season 4 in "The Puppy Episode," Ellen announced she was a lesbian. For the first one and a half seasons, Ellen lived in an apartment with roommate Adam. She lived alone after Adam moved out and then with her cousin Spence. Towards the end of season four, she bought her own house. Ellen's personality was likable and cheerful, but also somewhat clumsy and awkward, and with a persistent need to be liked. Her trademark behavior (and the main object of her comedy) was that she would digress in a rambling and babbling fashion, especially when nervous or embarrassed. An example of both her clumsiness and her need to please is found in the episode where she had Martha Stewart over for a dinner party and Ellen became highly stressed trying to organize the perfect dinner.
- Joely Fisher as Paige Clarke: Appearing in seasons two through five, Paige is Ellen's somewhat neurotic, vain and promiscuous best friend who works for a movie studio. Paige planned to tie the knot with her boyfriend Matt Liston, but dumped him at the altar after resuming an affair she had with Ellen's cousin Spence. When Ellen comes out of the closet, Paige has the hardest time dealing with it (even harder than Ellen's parents). In the fifth season, Paige finally comes to terms with it.
- Holly Fulger as Holly: Appearing only in the first season, including the two delayed episodes that aired during season three, Holly is Ellen's friend. Shy and self-conscious, she tries to avoid any trouble and is desperate to get along with the people around her. She actually would love to be in the center of attention, though she doesn't dare to overcome her shyness. Although her surname was never spoken or seen in the show it is actually revealed to be Jamison.
- Arye Gross as Adam Green: Appearing in seasons one through three, Adam is Ellen's roommate and they have been friends since college. A photographer, he is completely unsuccessful with women and is frequently dumped. In the middle of the third season, Adam moves to England to work as a photographer for The Sun Times, but upon his departure, he reveals that he was harboring a crush on Ellen. She in turn lies that she has one for him too, but he finds out the truth and that creates tension between the two of them until shortly before he leaves
- David Anthony Higgins as Joe Farrell: Appearing in all five seasons, Joe is a dour, sarcastic Canadian who works as the barista at the coffee shop inside Ellen's bookstore. His personal life is only touched upon, usually for comic relief in constant reference to misadventures he had in Moose Jaw. In the third season he becomes a member of the core group which aside from him consists of Ellen, Spence, Paige, and Audrey.
- Clea Lewis as Audrey Penney: Audrey is Ellen's squeaky-voiced and exceedingly perky neighbor and later co-worker, seen usually in the color pink and whose catchphrase was the enthusiastic greeting "Hi, Ellen!". Ellen has something of a love–hate relationship with Audrey, often annoyed at her overly upbeat demeanor. But after Ellen comes out, Audrey is extremely supportive (and excited, saying that she thinks "it's SUPER!"), and she throws herself into the LGBT culture, ironically with more reverence than Ellen did. In season one, Ellen refers to Audrey's husband, but he never appears and Audrey later dates several people, including Adam and Ron Palillo, who played himself over several episodes. It is revealed that she comes from a very well-off family, though she rejected her inheritance so that she could continue being an assistant at the bookstore. In her initial appearance in the first season she was not shown wearing pink and displayed less of the hyper and energetic personality the character eventually became in later seasons, she was much more of a negative character and blunt much to Ellen's chagrin although both of Audrey's personalities proved to be much of an annoyance to Ellen nonetheless.
- Jeremy Piven as Spence Kovak: Ellen's volatile but well-intentioned cousin from New York, who joined the cast in the third season. His arrival in Ellen's life coincides with the aftermath of a large Los Angeles earthquake that leads to the destruction and subsequent remodeling of the book store. Spence was training as a doctor, but was fired from his job for punching a patient and as a result spent the beginning of the third season bored and depressed. He begins training as a lawyer but after saving someone's life decides to resume his career in medicine. He and Paige had a love-hate relationship that began as constant fighting but later they became lovers and stayed such until a few episodes before the end of the series when the relationship ended amicably.
- Maggie Wheeler as Anita Warrell: Ellen's friend and a main character in the show's first season. Although she was one of the regular characters, much of her personality and past was never revealed, and she was under-utilized in the episodes she appeared in. She was mentioned by Holly to be much more attractive than her but, unlike Holly, most of her romantic relationships were never shown on screen although mentioned.
- Steven Gilborn as Harold Morgan: Ellen's father. He is often somewhat clueless about what is going on around him. At one point, he and Ellen's mother Lois announce that they want to divorce, much to Ellen's dismay. They later reconcile.
- Alice Hirson as Lois Ellington Morgan: Ellen's mother, Lois spends much of her time nosing and interfering in Ellen's life. Before Ellen comes out of the closet, Lois is obsessed with finding Ellen a husband. At one point, she wants to divorce her husband, but they later reconcile.
- Lisa Darr as Laurie Manning: Ellen's girlfriend. Laurie appears in eight episodes in the fifth and final season of Ellen. She and her daughter Holly (Kayla Murphy) become an increasingly important part of Ellen's life.
- Bruce Campbell as Ed Billik: Ed appeared in season four only as the new manager of Ellen's bookstore. He was a strict business type who frequently butted heads with Ellen over their management styles.
- Patrick Bristow as Peter Barnes: Ellen's gay best friend. He was a charity worker in the second season and a recurring role until the end of the series.
- Jack Plotnick as Barrett: Paige's assistant in season three. He was the love interest for Peter throughout the show.
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