Arrowsmith tells the story of bright and scientifically minded Martin Arrowsmith of Elk Mills, Winnemac, 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. Along the way he begins medical school. He becomes engaged to one woman, cheats on her with another woman, becomes engaged to the second woman and then finally invites both women to a lunch to settle the issue. Frustrated with the work, he moves on to a job as a public health official in Iowa, then becomes romantically involved with the young daughter of its local director. 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.

His scientific principles demand that he avoid its mass use on the Island until thoroughly tested, Even at the expense of lives that might be saved. Only after his wife, Leora, and all the other people who came with him from the institute to the island die of plague, does he reluctantly abandon rigorous science and begins to treat everyone on the island with the phage. While there he becomes romantically involved with a wealthy socialite, whom he later marries. In spite of his life- saving, he regards his actions on the island as a complete betrayal of science and his principles. Upon his return to New York he is heralded as a public hero for his actions on the island.

The book was popular and awarded a Pulitzer Prize in 1926 which was refused by Sinclair Lewis. He was later to win the Nobel Prize for Literature-which he accepted.