This complex novel is difficult to summarize. The main characters are introduced separately. We meet Yurii Andreievich Zhivago (Yura) when he is ten, at his mother’s funeral. He goes on to study medicine, write poetry, and marry a young woman named Tonya. We first encounter Larisa Foedorovna (Lara) as the adolescent daughter of a widow who has been set up in a dressmaking business by Komarovsky. Komarovsky later harasses and seduces the young woman. In her anger and guilt, the impulsive Lara tries to shoot Komarovsky at a grand Christmas party, but she misses and inadvertently wounds another man. Subsequently, Lara marries Pavel Pavlovich (Pasha), her childhood sweetheart.

All this takes place against the background of social upheaval in pre-World War I Russia. When the war begins, Yura joins the Army medical corps. Pasha leaves Lara and their daughter Tanya to enlist in the army. When Pasha is reported lost behind enemy lines, Lara becomes a military nurse in order to search for him. Thus, Lara and Yura meet at a hospital where his wife Tonya has just delivered a baby boy. Lara and Yura feel attracted to one another, but neither one expresses it. At this point the Revolution breaks out in Petersburg.

As the fighting rages, Lara and Yura are posted to a hospital in a small town, where Yura struggles with his feelings. When he reports his friendship with Lara, Tonya assumes incorrectly that they have become lovers. Over the winter there are food shortages and the threat of a typhus epidemic. As the war ends, Yura returns home to Moscow, and to his old job at the hospital, but his co-workers are suspicious of him. Influenced by Bolshevism, they dislike his use of intuition instead of logic. The family resolves to travel to the Urals. Amidst Marxist rebellions, Yura's family finds room in a cargo train. During the long train ride, Yura reflects on the suffering of peasants and prisoners caused by the revolution. He shares the desire for equality and freedom, but is disenchanted by the revolutionaries' pedantic, insensitive opinions.

The family safely arrives in the Urals and set up a farm. During the long winters, Yura returns to writing poetry. While visiting the local library, he re-encounters Lara. They begin an affair, sharing a common joy in a fully-lived existence. Lara is aware that her husband is still alive, having become a feared member of the Red faction under another name (Strelnikov). Yura resolves to tell his wife about his unfaithfulness and to ask forgiveness, but as he rides home, he is kidnapped by a faction in the Civil War (the Reds) and forced to serve as their doctor.

After some years, Yura escapes from the Reds and walks back to find Lara, who still lives in the same place.  To escape being informed upon, Lara and Yura flee to the farm house where Yura and his family once lived. Again, Yura turns to his poetry, expressing his fears, courage, and love for Lara. He learns that Tonya and a new baby daughter have been deported from Russia. One night, Lara's old lover, Komarovsky, appears and tells them that the triumphant revolutionaries know where they are and will inevitably kill them both. He offers to take them abroad, where Yura could rejoin his family. Yura refuses to accept help from Komarovsky. To save Lara's life, though, he tells her that he will follow them out of the country, but actually remains behind. Alone, he turns to drink.

One night Lara's husband, Strelnikov (Pasha), who is fleeing the new government, arrives. When he learns of Yura and Lara’s love, he leaves the house and shoots himself. Yura then goes to Moscow where he strikes up an affair with Marina and becomes a writer of literary booklets.  His brother finds him a job at a hospital, but on his way to his first day at work, he dies, presumably of a heart attack. Lara, who had been living in Irkutsk, has returned to Moscow and wanders accidentally into the house where his body lies waiting for burial. After several days, Lara disappears, presumably captured and sent to a concentration camp.