The film opens on a large cotton plantation called Tara in rural Georgia in 1861, on the eve of the American Civil War where Scarlett O'Hara (Vivien Leigh) is flirting with the two Tarleton brothers, Brent (Fred Crane) and Stuart (George Reeves). Scarlett, Suellen (Evelyn Keyes), and Careen (Ann Rutherford) are the three daughters of Irish immigrant Gerald O’Hara (Thomas Mitchell) and his wife, Ellen O'Hara (Barbara O'Neil), who is of aristocratic French ancestry. The brothers share a secret with Scarlett: Ashley Wilkes (Leslie Howard), whom Scarlett secretly loves, is to be married to his cousin, Melanie Hamilton (Olivia de Havilland). The engagement is to be announced the next day at a barbecue at Ashley's home, the nearby plantation Twelve Oaks.
At Twelve Oaks, Scarlett notices that she is being admired by a handsome but roguish visitor, Rhett Butler (Clark Gable), who had been disowned by his Charleston family. Rhett finds himself in further disfavor among the male guests when, during a discussion of the probability of war, he states that the South has no chance against the superior numbers and industrial might of the North. Scarlett sneaks out of her afternoon nap to be alone with Ashley in the library, and she confesses her love for him. He admits he finds Scarlett attractive, and that he has always secretly loved her back, but says that he and the sweet Melanie are more compatible. She accuses Ashley of misleading her to think that he did love her and slaps him in anger. Ashley silently exits and her anger continues when she realizes that Rhett was taking an afternoon nap on the couch in the library, and has overheard the whole conversation. "Sir, you are no gentleman!" she protests, to which he replies, "And you, miss, are no lady!" Nevertheless, Rhett promises to keep her guilty secret. Scarlett leaves the library in haste and the barbecue is disrupted by the announcement that war has broken out, so the men rush to enlist, and all the ladies are awakened from their naps. As Scarlett watches Ashley kiss Melanie goodbye from the upstairs window, Melanie’s shy young brother Charles Hamilton (Rand Brooks), with whom Scarlett had been innocently flirting, asks for her hand in marriage before he goes. Despite not truly loving Charles, Scarlett consents in order to get close to the family and make Ashley jealous. Charles and Scarlett are married before he leaves to fight.
Scarlett is quickly widowed when Charles dies from a bout with pneumonia and measles while serving in the Confederate Army. Scarlett's mother sends her to the Hamilton home in Atlanta to cheer her up, although the O’Haras' outspoken housemaid Mammy (Hattie McDaniel) tells Scarlett she knows she is going there only to wait for Ashley’s return. Scarlett and Melanie attend a charity bazaar in Atlanta; Scarlett, who should be buried in deep mourning, is turned against and whispered about. Rhett, now a heroic blockade runner for the Confederacy, makes a surprise appearance. Scarlett shocks Atlanta society even more by accepting Rhett's large bid for a dance. While they dance, Rhett tells her of his intention to win her, which she says will never happen, as long as she lives.
The tide of war turns against the Confederacy after the Battle of Gettysburg in which many of the men of Scarlett's town are killed. Scarlett makes another unsuccessful appeal to Ashley’s heart while he is visiting on Christmas furlough, although they do share a private and passionate kiss while in the parlor on Christmas Day, just before he leaves for the war. In the Hospital, Scarlett and Melanie care for the Reminiscent Soldier (Cliff Edwards).
Eight months later, as the city is besieged by the Union Army in the Atlanta Campaign, Melanie goes into a premature and difficult labor. Staying true to a promise Scarlett made to Ashley to "take care of Melanie," she and her young house servant Prissy (Butterfly McQueen) must deliver the child without medical attendance. Scarlett calls upon Rhett to bring her home to Tara immediately with Melanie, Prissy, and the baby. He appears with a horse and wagon to take them out of the city on a perilous journey through the burning depot and warehouse district. He leaves her with a nearly dead horse, helplessly sick Melanie, her baby, and tearful Prissy, and with a passionate kiss on the road leading to Tara. She repays him rudely with a slap, to his bemusement, as he goes off to fight with the Confederate Army. On her journey back home, Scarlett finds Twelve Oaks burned out, ruined and deserted. She is relieved to find Tara still standing but it has been deserted by all except her parents, her sisters, and two servants, Mammy and Pork (Oscar Polk). Scarlett learns that her mother has just died of typhoid fever and her father's mind has begun to crumble under the strain. With Tara pillaged by Union troops, and the fields untended, Scarlett vows she will do anything for the survival of her family and herself: "As God is my witness, I'll never be hungry again!"
The film's intermission is displayed after this.
Scarlett sets her family and servants to picking the cotton fields. She also kills a Union deserter who threatens her during a burglary, and finds gold coins in his haversack, enough to sustain her family and servants for a short time. With the defeat of the Confederacy and war's end, Ashley returns from being a prisoner of war. Mammy restrains Scarlett from running to him when he reunites with Melanie. The dispirited Ashley finds he is of little help to Tara, and when Scarlett begs him to run away with her, he confesses his desire for her and kisses her passionately, but says he cannot leave Melanie. Gerald O'Hara dies after he is thrown from his horse in an attempt to chase from his property a Yankee carpetbagger, the former overseer (Victor Jory) of his plantation who now wants to buy Tara. Scarlett is left to support the family, and realizes she cannot pay the rising taxes on Tara. Knowing that Rhett is in Atlanta and believing he is still rich, she has Mammy make an elaborate gown for her from her mother’s drapes still hanging in the parlor. However, upon her visit, Rhett, now in jail, tells her his foreign bank accounts have been blocked, and that her attempt to get his money has been in vain.
As Scarlett departs Rhett in jail, she encounters her sister’s fiancé, the middle-aged Frank Kennedy (Carroll Nye), who now owns a successful general store and lumber mill. Scarlett lies saying Suellen got tired of waiting and married another beau. After becoming Mrs. Frank Kennedy, Scarlett takes over his business, too and with the profits, buys a sawmill which becomes very profitable during the rebuilding of Atlanta—in part because she is willing to trade with the despised Yankee carpetbaggers and use convict laborers in her mill. When Ashley is about to take a job offer with a bank in the north, Scarlett preys on his weakness by weeping that she needs him to help run the mill; pressured by the sympathetic Melanie, he relents. One day, after Scarlett is attacked while driving alone through a nearby shantytown, Frank, Ashley, and others make a night raid on the shantytown. Ashley is wounded in a melee with Union troops, and Frank is killed.
With Frank’s funeral barely over, Rhett visits Scarlett, and proposes marriage. Scarlett takes him up on his offer, partially for his money. He kisses her passionately and tells her that he will win her love one day because they are both the same. After a honeymoon in New Orleans, Rhett promises to restore Tara to its former grandeur, while Scarlett builds the biggest mansion in Atlanta. The two have a daughter. Scarlett wants to name her Eugenie Victoria, but Rhett names her Bonnie Blue Butler (Cammie King). Rhett adores her as a symbol of the spirited but less grasping girl that Scarlett was before the war. He does everything to win the good opinion of Atlanta society for his daughter’s sake. Scarlett, still pining for Ashley and chagrined at the perceived ruin of her figure (her waist has gone from eighteen-and-a-half inches to twenty), lets Rhett know that she wants no more children and that they will no longer share a bed. In anger, he kicks open the door that separates their bedrooms to show her that she could not keep him away if he wanted to be with her.
When visiting the mill one day, Scarlett listens to a nostalgic Ashley, and when she consoles him with an embrace, they are spied by two gossips including Ashley's sister India (Alicia Rhett), who hates Scarlett. They eagerly spread the rumor and Scarlett’s reputation is again sullied. Later that night, Rhett, having heard the rumors, forces Scarlett out of bed and to attend a birthday party for Ashley. Incapable of believing anything bad of her beloved sister-in-law, Melanie stands by Scarlett's side so that all know that she believes the gossip to be false.
At home later that night, while trying to sneak a drink for herself, Scarlett finds Rhett downstairs drunk. Blind with jealousy, he tells Scarlett that he could kill her if he thought it would make her forget Ashley. Picking her up, he carries her up the stairs in his arms, telling her, "This is one night you're not turning me out." She awakens the next morning with a look of guilty pleasure, but Rhett returns to apologize for his behavior and offers a divorce, which Scarlett rejects saying it would be a disgrace. Rhett decides to take Bonnie on an extended trip to London. However, Rhett realizes later that as a little child, Bonnie still needs her mother by her side. This happened one night, when Bonnie cried in her nightmare and asked to be reconciled with her mother. Rhett returns with Bonnie, and Scarlett is delighted to see him, but he rebuffs her attempts at reconciliation. He remarks at how she looks different and she tells him that she is pregnant again. Rhett asks who the father is and Scarlett tells him he knows the baby is his and that she doesn't even want it. Hurt, Rhett tells her "Cheer up. Maybe you'll have an accident." Enraged, Scarlett lunges at him, falls down the stairs and suffers a miscarriage. Rhett, frantic with guilt, cries to Melanie about his jealousy, yet refrains from telling Melanie about Scarlett's true feelings for Ashley.
As Scarlett is recovering, little Bonnie, as impulsive as her grandfather, dies in a fall while attempting to jump a fence with her pony. Scarlett blames Rhett, and Rhett blames himself. Melanie visits the home to comfort them, and convinces Rhett to allow Bonnie to be laid to rest, but then collapses during a second pregnancy she was warned could kill her. On her deathbed, she asks Scarlett to look after Ashley for her, as Scarlett had looked after her for Ashley. With her dying breath, Melanie also tells Scarlett to be kind to Rhett, that he loves her. Outside, Ashley collapses in tears, helpless without his wife. Only then does Scarlett realize that she never could have meant anything to him, and that she had loved something that never really existed. She runs home to find Rhett packing to leave her, she begs him not to leave, telling him she realizes now that she had loved him all along, that she never really loved Ashley. However, he refuses, saying that with Bonnie's death went any chance of reconciliation. And when she repeats that she loves him, he states "That's your misfortune."
As Rhett walks out the door, planning to return to his hometown of Charleston, she pleads, "Rhett, if you go, where shall I go? What shall I do?" He famously answers, "Frankly, my dear, I don't give a damn" and walks away into the fog. She sits on her stairs and weeps in despair, "What is there that matters?" She then recalls the voices of Gerald, Ashley and Rhett, all of whom remind her that her strength comes from Tara itself. Hope lights Scarlett's face: "Tara! Home. I'll go home, and I'll think of some way to get him back! After all, tomorrow is another day!" In the finale, Scarlett stands once more, resolute, before Tara.
