- Drew Carey (Drew Carey): The main protagonist of the show. He is a dim-witted but kind-hearted comedian living in Cleveland, Ohio.
- Lewis Kiniski (Ryan Stiles): Drew's best friend and roommate, a sarcastic and intelligent everyman.
- Oswald Lee Harvey (Diedrich Bader): A dimwitted co-worker of Drew and Lewis with an inflated sense of self-importance.
- Mimi Bobeck (Kathy Kinney): A middle-aged woman and waitress at the local bar, who is known for her sharp tongue and outspoken personality.
- Kate O'Brien (Christa Miller): Drew's ex-girlfriend, who is a successful businesswoman and his friend.
- Steve Carey (John Carroll Lynch): Drew's cousin and a police officer.
- Mrs. Louella Klugman (Mo Collins): A nosy and gossiping neighbor of Drew and Lewis.
Supporting Characters:
- Vera Kiniski (Nanette Burstein): Lewis's mother, a Polish immigrant known for her traditional values and tough personality.
- Mr. Wick (Craig Ferguson): Drew and Lewis's eccentric Scottish landlord.
- Doris Klugman (Diedrich Bader): Mrs. Louella Klugman's dimwitted son.
- Sally Walker (Cynthia Stevenson): Kate's best friend and a love interest for Drew.
- Dr. Neal Miller (Robert Urich): Drew's therapist.
- Nicki Fifer (Lisa Banes): Kate's boss and Drew's eventual wife.
- Mr. Peterson (Ian Gomez): A coworker of Drew and Lewis who is known for his strict adherence to rules and regulations.
- Mrs. Evelyn Mitchell (Cloris Leachman): Drew's elderly and wealthy neighbor, who develops a crush on him.
- Joe Walsh (Himself): Drew's friend and a member of the rock band The Eagles, who makes occasional appearances in the show.