Two elderly men, blue-collar automotive mechanic Carter Chambers and billionaire Edward Cole meet for the first time in a hospital owned by Cole after both men are diagnosed with terminal lung cancer. Chambers, a gifted amateur historian and family man, wanted to become a history professor in his youth but chose to start a family instead. Cole, a four-time divorced healthcare tycoon and cultured loner, enjoys drinking kopi luwak, one of the most expensive coffees in the world and tormenting his personal valet Matthew, whom he mistakenly calls Thomas.
While in the hospital, Chambers and Cole manage to find common ground. For fun, Chambers started writing a list of activities to do before he "kicks the bucket." After hearing he has less than a year to live, he dejectedly discards his list. Cole finds it the next morning and urges him to do everything on the list, adds his own items to it and offers to finance all expenses. Chambers agrees and though his wife Virginia objects, the two patients begin their globetrotting last vacation. They go skydiving, drive a vintage Shelby Mustang and Dodge Challenger around California Speedway, fly over the North Pole, eat dinner at Chevre d'or, visit the Taj Mahal, ride motorcycles on the Great Wall of China, attend a lion safari in Tanzania and visit Mount Everest.
Atop the Great Pyramid of Giza, they confide mutually about faith and family. Chambers reveals that he has long been feeling less in love with his wife and feels some regret for his chosen path. Cole discloses that he is deeply hurt by his estrangement from his only daughter, who disowned him after he drove away her abusive husband. Later, while in Hong Kong, Cole hires a prostitute to approach Chambers, who has never been with any woman but his wife. Chambers declines and insists they stop the bucket list and go home.
During the return journey, Chambers tries to reunite Cole with his estranged daughter. Considering this a breach of trust, Cole angrily storms off. Chambers returns home to his family while Cole, feeling alone though among escorts, breaks down weeping in his luxury high-rise suite. Chambers' family reunion turns out to be short-lived as while readying for marital romance, he collapses and is rushed to the hospital, where it is discovered that the cancer has spread to his brain. Cole, now in a remarkable remission, visits him to reconcile. Chambers, always a Jeopardy! fan knowledgeable about trivia, reveals how Cole's kopi luwak coffee is fed to and defecated by a jungle cat before being harvested. As the two laugh hysterically over the obscure fact, Chambers implores Cole to finish the list for him.
After Chambers dies during surgery, Cole manages to reconcile with his own daughter and she introduces him to the granddaughter he never knew he had. After greeting the little girl by kissing her cheek, Cole thoughtfully crosses "kiss the most beautiful girl in the world" off the bucket list. Soon after, Cole delivers a eulogy at Chambers' funeral, during which he explains that the last three months of Chambers' life were, thanks to Chambers, the best three months of his own.
An epilogue reveals that Cole lived to age 81 and Matthew then took his ashes to a peak in the Himalayas. As Matthew places a Chock full o'Nuts coffee can of Cole's ashes alongside another can of Chambers' ashes, he crosses off the last item on the bucket list, "witness something truly majestic" and tucks the completed list between the cans.