The story is told in the third person, the central figure being Martin Arrowsmith, though Gottlieb occasionally takes the center of the stage. The narrative moves for the most part in a straight line chronologically, with few flashbacks but many changes of scene. The characters are the most lifelike that Lewis ever created, especially Martin, Gottlieb, and Leora. The Nobel Prize was awarded because Lewis was "significantly and typically American in his vision, humor, and creation of typical characters." Sometimes the humor of Arrowsmith is off-beat, like the macabre pranks played by the medical students on their classmates and others.
Most of the characters introduced early in the book reappear or are at least referred to years later, lending unity to the plot. Examples are the members of Digamma Pi, the Tozers, and Pickerbaugh. Character development and growth are apparent especially in Arrowsmith and Wickett, whose traits are deepened and emphasized with the passing years. In like manner, Clawson and Hinkley degenerate as they grow more mature. There is little change in Leora or Gottlieb. Romantic love is subordinated to quest for truth. Various social strata are introduced and satirized, from the shoddy farm and village characters of Wheatsylvania to the Rolls-Royce set of New York City. Singled out for special criticism is the Nautilus group, especially the Pickerbaugh family and Irving Watters.
Lewis' style, though not of highest literary quality, is yet vivid and readable. He has a tendency toward long sentences, probably in part a result of his wide reading of the nineteenth-century English and American novelists. Dorothy Thompson praised his use of verbs. She also commented that he put far more of himself into Arrowsmith than any other book. Lewis uses dialogue sparingly and background liberally, with figures of speech which make his sentences more graphic. The device of breaking each chapter into several divisions keeps the material from becoming too involved and stimulates reader interest.
The setting of Arrowsmith is American, except for the plague episode in British territory, the West Indies. From Elk Mills to Winnemac, from Zenith to Wheatsylvania, from Nautilus to New York, the scene shifts, each time portraying accurately and realistically a certain phase of life in the United States. Words that appeal to the senses — words of color, sound, shape, and motion, and even smell and taste — are used to make the effect more vivid.