Warren Schmidt (Jack Nicholson) has arrived at several of life’s crossroads all at the same time. He is retiring from a lifetime of service to an insurance company; his only daughter, Jeannie (Hope Davis), is about to get married; and his wife Helen (June Squibb) dies suddenly after 42 years of marriage. Desperate to find something meaningful in his thoroughly unimpressive life, Warren sets out on journey of self-discovery, exploring his roots across Nebraska in the 35-foot motor home. His ultimate destination is Denver, where he hopes to bridge the gulf between himself and his estranged daughter. Unfortunately, he hates the groom-to-be Randall (Dermot Mulroney), a profoundly mediocre, underachieving waterbed salesman. To make matters worse, Warren is appalled by his free-spirited and boorish soon-to-be in-laws (Kathy Bates and Howard Hesseman) and is swiftly convinced that his new purpose in life is to stop the marriage.

During this darkly comic and painful odyssey, Warren details his adventures and shares his observations with an unexpected new friend and confessor — Ndugu Umbo, a six-year-old Tanzanian orphan whom he sponsors for $22 a month through an organization that advertises on TV. From these long letters filled with a lifetime of things unsaid, Warren begins — perhaps for the first time — to glimpse himself and the life he has lived.