The film is set during World War II and depicts a critically burned man, at first known only as "the English patient", who is being looked after by Hana (Juliette Binoche), a French-Canadian nurse in a ruined Italian villa. The patient is reluctant to disclose any personal information but through a series of flashbacks, viewers are allowed into his past. It is slowly revealed that he is in fact a Hungarian geographer, Count László de Almásy (Ralph Fiennes), who was making a map of the Sahara Desert, and whose affair with a married woman (Kristin Scott Thomas) ultimately brought about his present situation. As the patient remembers more, David Caravaggio (Willem Dafoe), a Canadian thief/intelligence operative, arrives at the monastery. Caravaggio lost his thumbs while being interrogated by officers of the German Afrika Korps, and he gradually reveals that it was the patient's actions that had brought about his torture.

In addition to the patient's story, the film devotes time to Hana and her romance with Kip (Naveen Andrews), an Indian sapper in the British Army. Due to various events in her past, Hana believes that anyone who comes close to her is likely to die, and Kip's position as a bomb defuser makes their romance full of tension.