The series revolves around the life of Charlie Harper, his brother Alan, and Alan's son, Jake. Charlie is a bachelor who makes his money writing jingles for a living and leads a hedonistic lifestyle. When Alan's wife Judith decides to divorce him, Alan moves into Charlie's beach house, with ten-year-old Jake periodically coming to stay with his father and Charlie. Charlie's house is cleaned by Berta, a sharp-tongued woman who initially resists the change to the household but comes to grudgingly accept it.

At the beginning of season 9, the beach house is sold after Charlie's death to Walden Schmidt, an Internet billionaire in the process of being divorced by his wife Bridget. Although Alan leaves to live with his mother Evelyn after the house is sold, he is invited back to live in the beach house by Walden as he needs a friend to help guide him in the world. The effects of the changes going on after Charlie's death temporarily make Alan lose his sanity and believe himself to be Charlie.