The film takes place for the most part during the tumultuous period of 1913-1922, the years of World War I, the Russian Revolution, and Russian Civil War, as the regime of Emperor Nicholas II was overthrown and the Soviet Union established. A framing device, from which the film is narrated, takes place in the mid-to-late 1950's, though a specific date is not mentioned.

The film's framing device involves General Yevgraf Zhivago (Alec Guinness) searching for the love child of his brother, poet and Doctor Yuri Zhivago (Omar Sharif), and his mistress Larissa ("Lara") Antipova (Julie Christie); Yevgraf believes a young girl named Tonya Komarov (Rita Tushingham, referred to as "The Girl" in the credits) to be his niece. Yevgraf narrates the story, periodically appearing in it, though he does not ever interact with any other characters in the flashbacks.

Yevgraf tells the girl the story of his brother's life. Yuri's parents died at an early age, leaving him only a balalaika, and he went to live with the Gromekos - Alexander (Ralph Richardson) and Anna (Siobhan McKenna) - and their daughter Tonya (played as an adult by Geraldine Chaplin), who Zhivago later marries. Gromeko was a retired professor living in Moscow, and so Zhivago is able to enter medical school, studying under Professor Boris Kurt (Geoffrey Keen). Though he is already a poet of some renown, Yuri does not think that he can support himself with poetry and wishes to enter the medical profession. Lara, meanwhile, lives with her mother (Adrienne Corri), a seamstress who is being "advised" by Victor Komarovsky (Rod Steiger), a lawyer with political connections. (Komarovsky was also the friend and business partner of Zhivago's father.) Lara is also engaged to Pasha Antipov (Tom Courtenay), an idealistic revolutionary. Komarovsky takes Lara to a dress party and ultimately seduces her; Lara, somewhat reluctantly, becomes Komarovsky's mistress. Meanwhile, while Zhivago and the Gromekos watch, a demonstration led by Pasha is attacked by a detachment of dragoons, who wound Pasha and kill several others.

Lara becomes more deeply involved with Komarovsky, until her mother discovers their affair and tries to kill herself by swallowing iodine. Komarovsky summons help from Kurt and Zhivago, and Zhivago sees Lara for the first time. When Pasha, now a dedicated Bolshevik, tells Komarovsky that he intends to marry Lara, Komarovsky tries to dissuade Lara from doing so, and rapes her. In revenge, Lara takes a gun she had been hiding for Pasha, tracks Komarovsky down to a Christmas party (which Zhivago and Tonya are attending) and shoots him, before being escorted out by Pasha, who then learns of Lara's infidelity.

The movie then jumps ahead to August 1914: World War I. Yevgraf enlists, intending to subvert the war effort in order to start the Revolution; Yuri (now married to Tonya) and Professor Kurt become medical officers; and Pasha joins a volunteer regiment as well. Pasha is supposedly killed in a battle on the Eastern Front, and Lara becomes a nurse to look for him as the Revolution breaks out and the Russian army begins to desert en masse. Travelling with a group of deserters, Lara meets Zhivago, who is with a column of replacement troops; the soldiers mutiny and join the deserters, and Zhivago enlists the help of Lara to tend to their wounded. The two manage a makeshift hospital for the remainder of the war and are parted at war's end.

Yuri returns to Moscow, finding that Anna is dead and that the Gromeko's house has been apportioned to include several other families by the authorities. Yuri meets his son Sasha for the first time in years and resumes his old job at the local hospital, but is disgusted that his family is lacking in basic fuel and food. One night, while he tries to steal firewood for his family furnace, he is spotted by Yevgraf, who tracks him home. Yevgraf informs Zhivago and his family that they are under suspicion for subversive activities by the government and helps arrange for their transport to the Gromeko estate at Varykino, in the Urals.

Zhivago, Tonya, Sasha, and Alexander board a heavily guarded train which includes a detachment of labor conscripts - including hot-headed "intellectual" Kostoyed Amoursky (Klaus Kinski) - and a large contingent of Red Guard soldiers. At one point, the train passes through the village of Mink, which has been shelled by Red forces commanded by a General Strelnikov; at the end of Act One Strelnikov is revealed to be Pasha. While the Ural train is stopped, Zhivago wanders away from the train, listening to the sound of a water fall, and stumbles across Strelnikov's armored train. He is arrested and meets with Strelnikov - recognizing him as Pasha - who suspects him of being a hired assassin. After a tense conversation Strelnikov reveals that Lara is alive in the town of Yuriatin - which is currently occupied by forces of the White Army - and lets Zhivago go.

Zhivago's family arrives at Varykino but finds their main house to have been boarded up with a No Trespassing sign; however, they decide to occupy the spacious guest cottage. The family lives a mundane life until the next spring, when Zhivago goes into Yuriatin and runs into Lara at the local library. The two reacquaint themselves and consummate a sexual relationship. Zhivago is torn between Tonya and Lara, until Tonya becomes pregnant; Yuri travels to Yuriatin and breaks off his affair with Lara, only to be conscripted into service by Red partisan troops under Liberius (Gerard Tichy) while returning to Varykino.

After serving with the Partisans for nearly two years as a medical officer, Zhivago escapes, only to find that his family has left Varykino and emigrated to Paris; he goes to Lara's home in Yuriatin, and is ultimately discovered by Lara. The two renew their relationship, but Komarovsky arrives one night and informs them that they are being watched by the Bolsheviks, due to Lara's marriage to Strelnikov. Komarovsky offers Yuri and Lara his help in escaping, but they refuse; the two flee with Lara's daughter, Katya, to the Varykino cottage, which has been left open and frozen inside. Yuri begins working on the "Lara" poems, which would make him famous. Komarovsky reappears, telling Yuri that Strelnikov has been killed and that Lara is in immediate danger; Yuri sends Lara away with Komarovsky, but Zhivago remains behind.
Yuri ultimately dies in a Moscow street some years later, suffering a heart attack after seeing a woman he thought was Lara. Lara has become separated from the child of her and Yuri, and enlists Yevgraf's help; Yevgraf, however, is unable to find her daughter.

At the end of the story, the Girl leaves the meeting with Yevgraf with her boyfriend. Yevgraf notes the girl has a balalaika on her bike, and after being informed of the Girl's talents by her boyfriend, ascertains that she is indeed the daughter of Yuri and Lara.