Blue-collar mechanic Carter Chambers (Morgan Freeman) and billionaire hospital magnate Edward Cole (Jack Nicholson) meet for the first time in the hospital after both have been diagnosed with cancer. They become friends as they undergo their respective treatments. Carter is a gifted amateur historian and family man who had wanted to become a history professor, but in his youth had been "broke, black, and with a baby on the way" and thus never rose above his job at the McCreath (named after a healthcare consultant and friend of the writer) body shop. Cole is a corporate tycoon, eccentric loner, four times divorced, who enjoys nothing more than tormenting his personal valet/servant, Matthew, whom he calls Thomas (Sean Hayes). He quickly befriends Carter, making Matthew serve Carter as well as him and ordering his doctor (Rob Morrow) to familiarise himself with Carter's health.
Both are diagnosed with a year or less to live. Carter begins writing a "bucket list," or things to do before "he kicks the bucket." After hearing he has less than a year to live, Carter wads it up and tosses it on the floor. Matthew comes in the next morning and picks it up with other things that are on the floor. Cole finds it among the items and reads it. Cole pushes Carter (by suggesting he add things like seeing the world, sky diving, "fun things," etc.), and promises to finance the trip, as he is very wealthy. Despite the protests of his wife, Virginia (Beverly Todd), Carter eagerly agrees.
The pair then begin an around-the-world vacation, embarking on race car driving, sky diving, climbing the Pyramids, and going on lion safari in Africa. Along the way they discuss faith and family, and learn from each other that Carter has long been feeling less in love with his wife and Cole is deeply hurt by his estrangement with his only daughter, who disowned him after he sent some people to "take care" of her abusive husband.