Adrian Monk, a brilliant detective formerly with the San Francisco Police Department, struggles with obsessive-compulsive disorder (OCD) and various phobias. These conditions emerged after his wife, Trudy, was tragically murdered in a car bombing, a case that remains unsolved and haunts him. Monk's acute attention to detail and ability to notice minor inconsistencies provide him with a unique investigative edge. Despite his talents, his mental health issues often make everyday tasks difficult for him. Nevertheless, he works as a private consultant for the police department, solving cases that baffle the regular force. Captain Leland Stottlemeyer, head of the homicide division, values Monk's insights and frequently enlists his help, although he sometimes finds Monk's quirks challenging.

Monk is accompanied by his dedicated assistant, initially Sharona Fleming and later Natalie Teeger, who help manage his daily life and serve as intermediaries between his idiosyncrasies and the world. These assistants not only aid Monk with his investigations but also provide personal support, often acting as surrogate family members. His journey through various intriguing cases serves as both a means of coping with his loss and a hope to find answers about Trudy's death. Over time, Monk faces new challenges, wrestles with his fears, and gradually steps closer to resolving his greatest personal mystery. Despite the heavy themes, moments of humor often emerge from Monk's interactions with those around him and the peculiar situations generated by his disorder.