Warren Schmidt (Jack Nicholson) has arrived at several of life's crossroads all at the same time. To begin with, he is retiring from a lifetime of service as an actuary for Woodmen of the World Insurance Company, and he feels utterly adrift. Furthermore, his only daughter Jeannie (Hope Davis) is about to marry a boob. And his wife Helen (June Squibb) dies suddenly after 42 years of marriage.

With no job, no wife, and no family, Warren is desperate to find something meaningful in his thoroughly unimpressive life. He sets out on a journey of self-discovery, exploring his roots across Nebraska in the 35-foot motor home in which he had planned to drive around the country with his late wife. His ultimate destination is Denver, where he hopes to bridge the gulf between himself and his somewhat estranged daughter by arriving early to help with her wedding preparations. Unfortunately, he hates the groom-to-be Randall (Dermot Mulroney), a profoundly mediocre, mediocre, underachieving waterbed salesman. To make matters worse, Warren is appalled by the free-spirited nature and boorish behavior of his soon-to-be in-laws (Kathy Bates and Howard Hesseman). Warren grows swiftly convinced that his new purpose in life is to stop his daughter's 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.