Inherit the Wind is a fictionalized account of the 1925 Scopes "Monkey" Trial, which resulted in John T. Scopes's conviction for teaching Charles Darwin's theory of evolution to a high school science class, contrary to a Tennessee state law. The characters of Matthew Harrison Brady, Henry Drummond, Bertram Cates and E. K. Hornbeck correspond to the historical figures of William Jennings Bryan, Clarence Darrow, Scopes, and H. L. Mencken, respectively. However, the playwrights state in a note at the opening of the play that it is not meant to be a historical account, and there are numerous instances where events were substantially altered or invented. For instance, the characters of the preacher and his daughter were fictional, the townspeople were not hostile towards those who had come to Dayton for the trial, and Bryan offered to pay Scopes' fine if he was convicted. Bryan did die shortly after the trial, but it happened five days later in his sleep. Political commentator Steve Benen said of the play's inaccuracies: "Scopes issued no plea for empathy, there was no fiancee and the real Scopes was never arrested. In fact, the popular film that was nominated for four Academy Awards and has helped shape the American understanding of the 'Scopes Monkey Trial' for decades is an inadequate reflection of history." Lawrence explained in a 1996 interview that the drama's purpose was to criticize the then-current state of McCarthyism. The play was also intended to defend intellectual freedom. According to Lawrence, "we used the teaching of evolution as a parable, a metaphor for any kind of mind control [...] It's not about science versus religion. It's about the right to think."
The role of Matthew Harrison Brady is intended to reflect the personality and beliefs of William Jennings Bryan, while that of Henry Drummond is intended to be similar to that of Clarence Darrow. The character of E. K. Hornbeck is modeled on that of H. L. Mencken. Bryan and Darrow, formerly close friends, opposed one another at the Scopes trial, and Mencken covered the trial for The Baltimore Sun.