Arrowsmith by Sinclair Lewis is the story of Martin Arrowsmith, a young Midwestern boy who dreams of being a medical researcher. Martin's life and career are tested by affronts to his authenticity and view of perfect medicine. Martin's isolationist tendencies allow him few friends and very one-sided romantic attachments. Throughout his career Martin finds success but cannot allow himself to cross over from pure research to commercial medicine and ultimately gives up his job, wife and son in favor of research in a cabin in Vermont.

Martin Arrowsmith, born and raised in Elk Mills, Winnemac, discovers a love for medicine and research early in life while spending time in the office of the town's doctor, Doc Vickerson. Martin attends college and medical school at the University of Winnemac where he meets his mentor and life-long inspiration, Professor Max Gottlieb. During this time Martin also becomes a suitor to two young women, Madeline Fox and Leora Tozer. Martin marries Leora who is not quite as educated or sophisticated as Madeline but who loves Martin unconditionally and promises to support Martin's life goals.

Martin does his medical internship at a hospital in Zenith where he has his first encounters with the human side of medicine. From there, Martin and Leora move to Wheatsylvania, North Dakota, Leora's hometown, where Martin establishes a small medical practice. Unable to tolerate the small town life, the couple then moves to Nautilus, Iowa, where Martin takes a job as Assistant Director of Health for the city. Martin is tested by his boss, Dr. Almus Pickerbaugh, who is more of a carnival barker than a medical man.

Eventually Martin jumps at the chance to accept a position at the prestigious Rouncefield Clinic in Chicago and he and Leora make another move. One of Martin's colleagues, Angus Duer, is a surgeon at the clinic and tries to acclimate Martin to the lifestyle of an upwardly mobile physician but Martin's heart still lies with research, not with the financial gain which drives his colleagues at the clinic. Martin contacts Dr. Gottlieb who offers Martin a research position at the renowned McGurk Institute and Martin and Leora move to New York City.

Martin's work produces a huge breakthrough in isolating a bacteriophage that will kill the plague and pneumonia. Martin, along with Leora and a new colleague, Gustaf Sondelius, travel to the island of St. Hubert's in the Caribbean to test Martin's new phage. While on the island, Leora dies from the plague and Martin meets a wealthy widower, Joyce Lanyon, whom he marries after his return to New York. Martin and Joyce have a son they name John and Martin continues his scientific research in New York although he spends time with Terry Wickett, a former colleague from the McGurk Institute, who has set up a laboratory in the woods of Vermont.

Martin cannot adapt to Joyce's wealthy lifestyle and demands on Martin's time, so Martin leaves Joyce and John to move to Vermont where he will do his coveted research without the pressures from any other outside sources.