The novel begins with a brief vignette about Martin Arrowsmith's great- grandmother—a pioneer who wanted to see the world. She is "going west" in her wagon, with her mother dead and her father ill but remaining steadfast, nevertheless.
After this brief, one-paragraph episode, Sinclair Lewis begins the story of Martin Arrowsmith. When the reader first meets him he is fourteen and sitting in Doc Vickerson's office reading Gray's Anatomy in the small town of Elk Mills, Winnemac. Martin's father heads the New York Clothing Bazaar, but Martin prefers to spend his time with the doctor, reading his books and looking at the specimens of Doc Vickerson's museum of medical oddities. And, in fact, Lewis informs the reader that Martin, at the young age of fourteen, has become the doctor's unofficial assistant.
Doc Vickerson is an old widower who is fond of the drink. His office is not very clean, and the doctor is portrayed as somewhat of a mess who calls himself a failure. Nevertheless, he encourages Martin in the direction of education, knowledge, and medicine. And, by the end of the chapter, Doc Vickerson has given Martin the gift of a magnifying glass.
It is 1904, and Martin is a junior in college, preparing for Medical school at the University of Winnemac, which is fifteen miles from the largest city in Winnemac (Zenith). He appears to be a fairly handsome though thin boy that the girls all call "romantic"; he is also quite shy.
Martin has forgotten Doc Vickerson and Elk Mills and is completely enthralled by his life at the university. His new idol is the head of the chemistry department named Edward Edwards, whom all the students call "Encore." Martin is impressed by his knowledge and, mid chapter, finds himself at one of Edwards's "At Homes," where students and faculty confer and discuss. During this meeting, the strange German, Jewish professor Max Gottlieb comes up in conversation. Gottlieb is known for his brilliant and difficult-to-understand research in Immunology and is shrouded with campus rumors and mystery that excites Martin. After the gathering, Martin goes to the medical school campus and sees Max Gottlieb leaving the lab late at night and is taken in a gust of admiration.
Soon after, Martin enters medical school feeling superior and yet, nervous. He goes to Gottlieb and tells the professor that he would like to take his bacteriology class, but Gottlieb tells him that he must come back the next year after he has taken physical chemistry. Martin is disappointed and thinks about his encounter with Gottlieb, and he begins to wonder if Edward Edwards was really as intelligent as he had once thought. Furthermore, Martin has begun to question "truth."