Martin Arrowsmith, of pioneer descent and unflagging spirit, begins his medical training by reading Gray's Anatomy at the age of fourteen in the office of Doc Vickerson, of Elk Mills. In 1904, he enters Winnemac University, where during his career as a student he becomes assistant to Max Gottlieb, a German scientist, whom Martin deeply admires and respects. Digamma Pi is the fraternity through which Martin becomes acquainted with other students who are to reappear later in the story, notably Clif Clawson, Ira Hinkley, Angus Duer, and Irving Watters. During his years at Winnemac, Martin falls in love with a probationary nurse, Leora Tozer, and marries her a year before graduation in Wheatsylvania, North Dakota. With the financial help of her unwilling family, they return to Winnemac, and Martin receives his medical degree, becoming an intern in Zenith General Hospital.
His internship over, Martin opens an office in Wheatsylvania, Leora's home town, and does general practice for two years. Always, however, his heart is in laboratory work.
Max Gottlieb loses his position on the faculty of Winnemac and joins the Hunziker Pharmaceutical Company of Pittsburgh, an institution criticized for unethical practices. Martin is disappointed that his former professor has formed such an alliance. The Tozer family and the general unpleasant surroundings cause Martin to welcome a chance to move on. This chance comes through his acquaintance with Dr. Gustaf Sondelius, Swedish physician and lecturer, who helps the young man obtain a position in Nautilus.
Martin's director in Nautilus, a town of seventy thousand, is Dr. Almus Pickerbaugh, head of the Department of Public Health, whose family consists of his wife and eight daughters. The oldest, Orchid, greatly admires the young physician. Martin is disappointed, however, when he learns that a load of trivial duties will almost exclude any intensive laboratory work. In Nautilus, Dr. Irving Watters, formerly of Digamma Pi, is now a leading practitioner.
Pickerbaugh is nominated for Congress, and Martin takes charge of the department while the candidate is campaigning. Pickerbaugh is elected, and his leaving for Washington is celebrated lavishly. Martin, too eager to free the town of rats, fleas, and disease, incurs the disfavor of the authorities and is practically forced to resign. He writes to Angus Duer in Chicago.
Duer, now a highly successful surgeon, employs Martin in Rouncefield Clinic. For a year, he is an impersonal part of a large organization. Then an article which he publishes in a medical journal attracts the attention of Max Gottlieb, now a research scientist at McGurk Institute in New York. He offers Martin a position in laboratory work, which the young man accepts.
Gottlieb advises Martin to study mathematics and physical chemistry in order to prove his own experiments. On the McGurk staff are also Dr. Rippleton Holabird, status-seeking head of the department of physiology; Dr. Terry Wickett, a rude and irritating seeker for scientific truth; and Dr. Tubbs, Director of the Institute.
America enters World War I in 1917, and work at the Institute is diverted to the war effort. Gottlieb is unkindly treated because of his German background.
Martin's experiments with laboratory cultures are dramatic. He discovers an X Principle, which will fight and control a number of diseases. A French scientist, D'Hérelle, of Pasteur Institute in Paris, has made the same discovery, however, and his results are publicized before Martin's. Consequently Martin loses the credit and can only corroborate the findings of D'Hérelle.
A year passes before the bubonic plague breaks out in St. Hubert, an island in the West Indies. Sondelius reappears and joins the staff of McGurk. He and Martin become collaborators in search of a cure for the plague. They are appointed by the Institute to go to St. Hubert and experiment with the phage. Leora insists on going along. Sondelius is to be charge of sanitation, and Martin is to do the actual testing. Both have explicit instructions from Gottlieb as to their procedures.
Conditions are much worse than expected on St. Hubert. Martin wishes that he had forced Leora to stay behind. He conducts his experiment but loses Leora and Sondelius, both of whom die of the plague. Ira Hinkley, who reappears in the West Indies, is also a victim. At the home of an official, Martin meets Joyce Lanyon, who is later to become his second wife. The plague is halted, and Martin returns to New York alone, where he is received with much acclaim by the press, the Public Health Service, and, of course, McGurk Institute.
Martin's subsequent marriage to Joyce Lanyon brings him into a social world where the emphasis is on money and position rather than on search for truth. After several years of the marriage, during which a son, John Arrowsmith, is born, Martin leaves Joyce to join Terry Wickett in the Vermont hills, where, with a few other research men, they can pursue their laboratory work in seclusion and peace. Joyce will probably divorce her husband and marry Latham Ireland, a friend of her first husband, Roger Lanyon. So ends the story of Arrowsmith.