Based on Graham Greene's novel Stamboul Train, the movie focuses on the lives of individuals aboard the Orient Express as it makes a three-day journey from Ostend to Constantinople.

Two sisters from Indiana, the wide-eyed and innocent Mae Thorpe, and her more streetwise sister June, move into the Rolf House for Homeless Girls in New York. With June's help, Mae obtains a job as a stenographer for the scientist Joseph von Schraeder, while June gets work as a telegraph operator at Western Union.

When World War I breaks out, brothers Roy and Monte Rutledge, each attending Oxford university, enlist with the Royal Flying Corps.