The show revolves around the day-to-day life of Jessica Fletcher (née MacGill), a widowed and retired English teacher, who becomes a successful mystery writer. Despite fame and fortune, Jessica remains a resident of Cabot Cove, a small coastal community in Maine, and maintains her links with all of her old friends, never letting her success go to her head.

The show usually starts with a preview of the episode's events, with Jessica stating: "Tonight on Murder, She Wrote..." Jessica invariably proves more perceptive than the official investigators of a case, who are almost always willing to arrest the most likely suspect. By carefully piecing the clues together and asking astute questions, she leads the authorities to arrest the real murderer. Murder occurred with such regularity in her vicinity that the term "Cabot Cove syndrome" was coined to describe the constant appearance of dead bodies in remote locations. Indeed, if Cabot Cove existed in real life, it would top the FBI's national crime statistics in numerous categories, with some analysis suggesting that the homicide rate in Cabot Cove exceeds even that of the real-life murder capital of the world.

Jessica's relationship with law enforcement officials varies from place to place. Both sheriffs of Cabot Cove resign themselves to having her meddle in their cases. However, most detectives and police officers do not want her anywhere near their crime scenes, until her accurate deductions convince them to listen to her. Some are happy to have her assistance from the start, often because they are fans of her books. With time, she makes friends in many police departments across the U.S., as well as with a British police officer attached to Scotland Yard. At the start of season eight, more of the stories were set in New York City with Jessica moving into an apartment there part-time in order to teach criminology.