Psychiatrist Dr. Frasier Crane (Grammer) returns to his home town of Seattle, Washington, following the end of his marriage and his life in Boston (as seen in Cheers). His plans for a new life as a bachelor are challenged when he is obliged to take in his father, Martin (Mahoney), a retired Seattle Police Department detective, who has mobility problems after being shot in the line of duty during a robbery.
Frasier hires Daphne Moon (Leeves) as Martin's live-in physical therapist and caregiver, and tolerates Martin's dog Eddie. Frasier frequently spends time with his younger brother Niles (Pierce), a fellow psychiatrist. Niles becomes attracted to, and eventually falls in love with, Daphne (notwithstanding his own marriage), but does not confess his feelings to her until the final episode of the seventh season.
Frasier hosts The Dr. Frasier Crane Show, a call-in psychiatry show on talk radio station KACL. His producer Roz Doyle (Gilpin) is very different from Frasier in many ways. She is working class, has cheap tastes and, at least early in the series, has superficial relationships with many men. However, Roz and Frasier share a professional respect, and over time, they become best friends. Frasier and the others often visit the local coffee shop, Café Nervosa.
The Crane sons, who possess expensive tastes, intellectual interests, and high opinions of themselves, frequently clash with their blue-collar, Average Joe father. The brothers' close relationship is often tense, and their sibling rivalry intermittently results in chaos. Other recurring themes include Niles' relationship with his never-seen wife (later ex-wife) Maris, Frasier's search for love, Martin's new life after retirement, and the various attempts by the two brothers to gain acceptance into Seattle's cultural elite.
The main cast remained unchanged for all 11 years. When the series ended in 2004, Grammer had portrayed the character of Frasier Crane for a total of 20 years, including his nine seasons on Cheers; at the time, he tied James Arness' portrayal of Matt Dillon on Gunsmoke for the longest-running character on primetime television. The record has since been surpassed in animation by the voice cast of The Simpsons, and in live action by Richard Belzer's portrayal of John Munch on the series Homicide: Life on the Street and Law & Order: Special Victims Unit. Grammer was briefly the highest-paid television actor in the United States for his portrayal of Frasier, while Jane Leeves was the highest-paid British actress.