Arrowsmith tells the story of bright and scientifically minded Martin Arrowsmith of Elk Mills, Winnemac (the same fictional state in which several of Lewis's other novels are set), as he makes his way from a small town in the Midwest to the upper echelons of the scientific community at a prestigious foundation in New York City.

Frustrated with the work, he moves on to a job at the state Department of Public Health branch in Nautilus, Iowa, then becomes romantically involved with the young daughter of its local director.

Finally, Arrowsmith is recognized by his former mentor, Gottlieb, for a scientific paper he has written, and is invited to take a post with a wealthy and elite research institute in New York City.

The book's climax deals with Arrowsmith's discovery of a phage that destroys bacteria and his experiences as he faces an outbreak of bubonic plague on a fictional Caribbean island.

He turns down the promotion, then abandons his new wife and infant son to work in the backwoods of Vermont as an entirely independent scientist.

The attractions of financial security, recognition, even wealth and power, lure Arrowsmith away from following the footsteps of his first mentor, the brilliant but abrasive bacteriologist Max Gottlieb.

Professional jealousy, institutional pressures, greed, stupidity, and negligence are all satirically depicted, and Arrowsmith himself is exasperatingly self-involved.

[3] Educator and school founder Lisa VanDamme describes using the ethical challenges and world outlook presented in Arrowsmith: “…I might give one class about the idealistic characters and in what way they are doomed to suffering in the world, another about those who abandon their ideals and achieve practical ‘success,’ another about the basic moral-practical dichotomy this implies, and another contrasting this view with that of…[other novelists].”[4] Arrowsmith has been compared with The Citadel, published in 1937 by A. J. Cronin, which also deals with the experiences of a young idealistic doctor who tries to challenge and improve the existing system of medical practice.

Sinclair’s scientific collaborator Paul de Kruif drew inspiration for locations and characters in Arrowsmith from specific sources.

The laboratory work and experimental process of Max Gottlieb was based on the careers of Frederick George Novy and Jacques Loeb.

[8]The New York Times reported that, according to observers, the real reason was that Lewis was still upset that Main Street did not win the prize in 1921.

[10][11] Helen Hayes reprised her role as Leora in an hour-long adaptation on The Campbell Playhouse radio program along with Orson Welles as Arrowsmith.