Charles Francis Harper (Charlie Sheen) is a successful 40-year-old bachelor who has a career writing advertising jingles. Charlie resides in a large, oceanfront home in Malibu, California, and is portrayed as an immature, hedonistic womanizer-all he seems to care about is having sex. The plot begins when his younger brother Alan (Jon Cryer) separates from his wife (Marin Hinkle) and has to move in with his brother. Alan shares custody of his son, Jake (Angus T. Jones) (aged 10 at the beginning), who stays with him part-time. Charlie, Alan, and Jake are the "Two and a Half Men" referenced by the title.

Charlie and his neighbor, self-confessed stalker, Rose (Melanie Lynskey), had a one night stand shortly before the show started. She tends to sneak into the house (usually climbing over the railing of Charlie's deck) at all times of the day or night. She freely expresses her love for Charlie, and despite her apparent issues is often a good, albeit crazy, friend and adviser. Although obviously troubled herself, Rose apparently has a Master's degree in psychology, and Alan has mentioned she has two advanced degrees. In various episodes it is insinuated that Rose is orchestrating a complex plan to win Charlie from himself. Early in the series she becomes Scrabble friends with Alan, and is heard to say to herself, "Phase one, complete." After Charlie and Alan's mother, Evelyn (Holland Taylor), and Rose's father, Harvey (Martin Sheen), meet (and Harvey begins stalking her like Rose stalks Charlie), Rose's Grandmother exclaims "That's what happens when you marry a first cousin!" as an explanation for the family's dementia.

Another important recurring character is Berta (Conchata Ferrell), Charlie's sarcastic and sharp-tongued housekeeper. She trades insults with Charlie and Alan. Alan's penchant for particular food products often triggers Berta's wit. She frequently refers to him as "Zippy." Berta also enjoys starting trouble between the brothers by needling each one about the other.

Alan and Charlie's controlling mother, Evelyn, is a real estate agent in her early-60s. She's rich, hip, and many-times-divorced, with huge appetites for money and sex. Both Charlie and Alan attribute many of their problems to their impersonal upbringing, adding to the caustic humor of the show when the brothers and the mother interact. Evelyn is often referred to as "the devil." Despite her selfishness and narcissism, Evelyn professes to love her sons and grandson deep down.

Another recurring theme is the conflict of personalities between the two siblings: the relaxed, hedonistic, immature Charlie, and the self-conscious, responsible, worrying Alan. Alan is often exasperated with Charlie's lifestyle, and sometimes tries to intercede in Charlie's bad decision-making. This also provides opportunities for comedy in the show, with Alan admitting defeat with such comments as "It's like talking to a horny chimp." Every season has at least one episode where Charlie and Alan are seriously fighting with each other, although the conflicts are generally resolved by that episode's end.

A great deal of the humor on the show comes from the real-life experiences of creator Chuck Lorre. In a now-famous "Entertainment Weekly" interview, Holland Taylor said that Lorre was using the memories of his own less-than-great relationship with his mother for the story lines involving Evelyn, Charlie, and Alan. It is a common misconception that the show is based on Sheen's life as it was reported in many tabloids shortly after pilot was aired. Charlie Sheen also said that it was "no accident...that Chuck finally decided to do a show about men. I'll leave it at that."

In all but two episodes, the title of the episode is a quote from the show. The exceptions are the pilot and another episode where the quote in question was part of a deleted scene. (See: List of Two and a Half Men episodes)

The show is also filmed on the '70s sitcom "Laverne and Shirley" set, after the Laverne and Shirley characters moved to California. The only big changes in the set are a small hallway at the base of the stairs, and the kitchen is slightly larger.