[1][2] Based on a story by Leslie Charteris, the film is about a woman who witnesses a murder in a nearby building from her train window.

After she reports the murder to the police, who quickly dismiss her story, she turns to a popular mystery writer to help her solve the crime.

Before reaching Grand Central, Nicki's train makes a brief stop and, when she looks up from the book she is reading – a mystery by novelist Wayne Morgan – she witnesses a murder in a nearby building.

Upon arrival, she slips away from Haskell and goes to the police, but the desk sergeant, seeing the novel in her hand, assumes she imagined the crime.

Following Morgan and his fiancée into a theater, she sees a newsreel about the "accidental" death of shipping magnate Josiah Waring—and recognizes him as the murder victim.

Nicki snoops around the house and absconds with a pair of bloody slippers that disprove the story of an accident.

Two conspirators in the murder try but fail to stop her: Saunders, who turns out to be the nightclub's manager and another heir, and the chauffeur, Danny.

Back with Haskell, Nicki makes another attempt to involve Morgan, phoning him and pretending a man is there attacking her—not realizing that Danny is there and is about to do just that.

He and Danny admit their involvement in the murder and threaten her, but Morgan breaks into the room and Nicki takes the slippers back.

[4] The film was part of an attempt by producer Felix Jackson to diversify Durbin's image, that also included Christmas Holiday.

The executive producer of Return of the Saint, Robert S Baker, said that Leslie Charteris was surprised on reading the "Signal Stop" script, noting its similarity with Lady on a Train.

[12] In the 1960 Peter Gunn episode "The Passenger", a man witnesses a murder in a hotel room from a bus window and is initially disbelieved.