The story is the life of idealistic doctor Martin Arrowsmith (Colman). Arrowsmith goes to medical school and shows great promise as a research scientist, but elects to go into private practice in a small town to support his new wife Leora (Hayes). Eventually Arrowsmith gets a job at the McGurk Institute in New York. There his research into The Black Death (that is, The Plague, Yersinia pestis) leads him to discover a bacteriophage (a "serum") that will cure the illness. When an outbreak of bubonic plague hits the West Indies, Arrowsmith goes there in order to contain and cure the illness, with Leora tagging along.
Lewis declined the Pulitzer Prize awarded to him, citing a concern with writing to win awards. The film by John Ford itself received four Academy Award nominations.
- The Artifact: Joyce Lanyon, as played by Myrna Loy in the film. In the novel, she becomes Martin's second wife. In the film, pretty much the whole story after Arrowsmith's return from the West Indies is omitted, and the character of Joyce as played by Loy kind of stands around for a while with nothing to do.
- As You Know: "I have sent for you, Martin, to tell you that I am leaving this place where I teach young doctors to cure their patients."
- The Black Death: Running rampant in the Caribbean. Truth in Television as localized outbreaks of the plague were still relatively frequent in the early 20th century.
- Drowning My Sorrows: Martin gets roaring drunk after finding out that his wife has died of plague.
- Failed a Spot Check: Not only is Arrowsmith shockingly casual with his plague cultures, carrying them around in open test tube racks, but he fails to notice that one is leaking. This leads to his wife's death.
- Family Theme Naming: For a time, Arrowsmith works for Almus Pickerbaugh, the Director of Public Health in the city of Nautilus, Iowa. Pickerbaugh has eight daughters, all named after flowers: Orchid, Verbena, Daisy, Jonquil, Hibisca, Narcissa, and the twins, Arbuta and Gladiola.
- Happily Married: Martin and his first wife, Leora. (As opposed to most marriages in Sinclair Lewis novels).
- Like a Son to Me: Arrowsmith's mentor Dr. Gottlieb says this about him right before Gottlieb has a stroke.
- Lockdown: The whole West Indies are under quarantine.
- Love at First Sight: Martin asks Leora to marry him, and she accepts, on their first date."Of course it's a little bit early in the game to be dead sure."
- A Minor Kidroduction: Martin Arrowsmith is introduced as a teenager with dreams of medicine.
- No Communities Were Harmed: Because Sinclair Lewis received so much flak from the residents of the actual city of Sauk Centre, Minnesota who didn't like their town's presentation in his earlier book Main Street, Lewis sets part of the story in the fictional city of Zenith, Winnemac, (and the nearby Winnemac State University at Mohalis) for this and all works he wrote after Main Street.
- Not Even Bothering with the Accent: Ronald Colman, playing a small-town American doctor with his velvety British accent.
- Pietà Plagiarism: Martin cradling his wife's body after finding her on the floor, dead of plague.
- Pragmatic Adaptation: The latter portion of the book, namely Martin marrying high-society Joyce and being distracted from his research, is excised from the film.
- Protagonist Title: One of the several examples from Sinclair Lewis.
- Reality Has No Subtitles: A whole scene aboard a Swedish ship, as the crew realizes they are carrying plague.
- Technicolor Science: In a black-and-white film, but the principle of many exotic flasks filled with dark-colored, bubbling liquids is the same.
- Tested on Humans: What Arrowsmith plans to do when he arrives in the Caribbean—test the effectiveness of his serum by giving it to half the people and seeing how well it works. The authorities in the West Indies, who don't want to die, don't like this plan at all.
- Witch Doctor: Upon arriving at Dr. Marchand's island, Arrowsmith and the others find the locals performing voodoo rituals to ward off the sickness. A rueful Dr. Sondelius says they're doing about as much good as Western medicine is.