The novel's historical backdrop is the North African/Italian Campaigns of World War II. The story is told out of sequence, moving back and forth between the severely burned "English" patient's memories from before his accident and current events at the bomb-damaged Villa San Girolamo (in Fiesole), an Italian monastery, where he is being cared for by Hana, a troubled young Canadian Army nurse. The English patient's only possession is a well-worn and heavily annotated copy of Herodotus's The Histories that has survived the fiery parachute drop. Hearing the book constantly being read aloud to him brings about detailed recollections of his desert explorations, yet he is unable to recall his own name. Instead, he chooses to believe the assumption by others that he is an Englishman based on the sound of his voice. The patient is in fact László de Almásy, a Hungarian Count and desert explorer, one of many members of a British cartography group.
Caravaggio, an Italian-Canadian in the British foreign intelligence service since the late 1930s, befriended Hana's father before the latter died in the war. He learns that Hana is at the villa caring for a patient. He had remained in North Africa to spy when the German forces gain control and then transfers to Italy. He is eventually caught, interrogated, and tortured; they even cut off his thumbs. Caravaggio bears physical and psychological scars from his painful war experience for which he seeks vengeance.
Two British soldiers yell at Hana to stop her from playing a piano since the Germans often booby-trapped them. One of the soldiers, Kip, an Indian Sikh, a trained sapper, specializes in bomb and ordnance disposal. Kip decides to stay at the villa to attempt to clear it of unexploded ordnance. Kip and the English patient immediately become friends.
The English patient, sedated by morphine, begins to reveal everything: he fell in love with the Englishwoman Katharine Clifton who, with her husband Geoffrey, accompanied Almásy's desert exploration team. Almásy was mesmerized by Katharine's voice as she read Herodotus' Histories out loud by the campfire. They soon began a very intense affair, but she cut it short, claiming that Geoffrey would go mad if he were to discover them.
Geoffrey offers to return Almásy to Cairo on his plane since the expedition will break camp with the coming of war. Almásy is unaware that Katharine is aboard the plane as it flies low over him and then crashes. Geoffrey is killed outright. Katharine is injured internally and Almásy leaves her in the Cave of Swimmers. Caravaggio tells Almásy that British Intelligence knew about the affair. Almásy makes a three-day trek to British-controlled El Taj for help. When he arrives, he is detained as a spy because of his name, despite telling them about Katharine's predicament. He later guides German spies across the desert to Cairo. Almásy retrieves Katharine's dead body from the Cave and, while flying back, the decrepit plane leaks oil onto him and both of them catch fire. He parachutes from the plane and is found severely burned by the Bedouin.
The novel ends with Kip learning that the U.S. has bombed Hiroshima and Nagasaki. He departs from Villa San Girolamo, estranged from his white companions.