Inherit the Wind opens in the small town of Hillsboro, where a little boy named Howard teases a little girl named Melinda about once being a worm. Soon, a young woman named Rachel enters the courthouse square and asks a bailiff named Meeker if she can see Bert Cates. This visit is a secret from her father, a minister. Bert and Rachel speak in the courtroom, and Rachel urges him to confess to wrongdoing, for Matthew Harrison Brady is coming to prosecute him. Cates holds that he did nothing wrong by teaching the Darwinian theory of evolution to his students.
In the square, the townspeople prepare for the arrival of Brady, a three-time Presidential candidate, readying the things they will sell and preparing a banner that says "Read Your Bible!" A cynical reporter named Hornbeck from Baltimore comments on the surroundings. Brady arrives on the train with his wife Sarah and is welcomed by the mayor and Rev. Brown, as well as a crowd of townspeople and press. At a picnic in Brady's honor, Hornbeck informs him that he will be arguing against Henry Drummond in court. Brown rails against Drummond as an evil defender of the guilty and desperately seeks a way to bar him from town. The crowd moves off, and Hornbeck speaks to Rachel, showing her an article he has written that will help Cates. Rachel remains conflicted. When she has left, Drummond arrives, bathed in shadow, and is mistaken for the devil by little Melinda.
The next day, in the courtroom, juror selection is just finishing. Brady seeks witnesses who profess strong religious belief and cannot help but begin making speeches against Cates already. Drummond looks for jurors with open minds, including an illiterate man who has read neither the Bible nor Darwin. The judge recesses the court after an argument about this juror and announces a prayer meeting that evening, which Drummond finds prejudicial. After the others leave, Drummond, Rachel, and Cates speak. The townspeople are more angry at Cates for killing an "old wives tale" than they were at a wife-killer who was imprisoned in the town jail. Drummond tells Cates if he truly believes he has done wrong, he will change his plea, but Cates stands firm. When Cates leaves, Rachel reveals Brady is making her testify and that she is terrified of her father. Drummond tells her it takes strength to stand by a great man like Cates.
On the courthouse lawn that night, Brady leads an impromptu press conference before the prayer meeting. Brown begins preaching to a fervent crowd, retelling the Creation story and then condemning Cates as a sinner and calling down God's wrath upon him. When he condemns any who help Cates, including his own daughter, Brady stops him, quoting Solomon, "He that troubleth his own house shall inherit the wind," and speaking of a God of forgiveness. The meeting disbands and Brady asks his friend Drummond how he has moved so far away from him. Drummond says that Brady has moved away by standing still.
Two days later, Howard is on the witness stand, testifying about being taught evolution by Cates in school. Brady makes a speech about the boy being torn from his faith by the teachings of science. When Drummond questions him, Howard says he wasn't hurt and that he needs to think more about what Cates taught. Drummond argues that the right to think is on trial. Davenport calls Rachel next, and she testifies that Cates dropped out of church two years ago, after her father testified that a little boy who died without being baptized was damned to hell. Brady twists her words about things Cates has told her and finally she breaks down on the stand. Brady dismisses her, and at Cates' urging, Drummond says he has no questions for her. The prosecution rests.
The defense opens its case by calling experts on evolution, zoology, and anthropology, but the judge upholds Brady's objections to all of them, saying that the townspeople have already stated, through their law, that they don't want to hear about evolution. A desperate Drummond calls Brady to the stand to testify on the Bible. Brady's pride leads him to answer Drummond's challenge. His faith reveals him to be closed-minded and he has no answers about Biblical incidents that contradict natural law back to Copernicus, demonstrating him to be more unthinking and unquestioning than faithful. He challengeds Drummond's holiness, and Drummond says that he finds the individual human mind holy. Finally, he admits that the "days" of Creation need not have been twenty-four hour days at all. But Brady goes too far, saying he knows that Darwin is wrong because God speaks to him and he acts accordingly. Drummond mocks Brady's presentation of himself as a prophet. When the courtroom clears, a shaking Brady worries that the crowd laughed at him and is comforted by his wife.
The next day, Cates and Drummond await the jury's return, while Brady drowns his sorrows with food. Cates worries about what will happen to him, and Drummond compares practicing law to horse racing, reminiscing about a shiny rocking horse from his childhood that turned out to be rotten inside. The mayor warns the judge about a wire from the state capitol about the effect of the verdict on upcoming elections. Meanwhile, a radio man prepares his equipment to broadcast the verdict. Court reconvenes, and the jury has unanimously found Cates guilty. In the rush, the judge almost forgets to let Cates make a statement. He does, standing up for his actions and saying he did no wrong. The judge passes sentence on Cates merely a hundred dollar fine. Drummond says that nonetheless they will appeal.
The judge adjourns court, telling Brady he will have to make his speech after the trial concludes. Brady speaks but in the bustle of talk and movement and buying lemonade, few people listen. Finally, the radio man introduces a music program and leaves as well. Brady suddenly goes silent and collapses. He is carried out of the courtroom to the doctors, reciting the Inaugural Address he never had the chance to give. Drummond tells Cates he won in the eyes of the nation. Meeker tells Cates that Hornbeck paid his bail.
Rachel rushes in, telling Cates she has read Darwin and realizes she should not be afraid to think. The judge returns, announcing that Brady is dead. Hornbeck and Drummond argue Brady, Hornbeck calling him ignorant and Drummond calling him a misguided great man. They agree that the words he spoke to Rev. Brown were a fitting epitaph for him. Rachel and Cates decide to leave together on the same train that Drummond will take. At the end, Drummond is left alone in the courtroom with a copy of Darwin and copy of the Bible, which he puts together in their briefcase.