Main Street was initially awarded the 1921 Pulitzer Prize for literature, but was rejected by the Board of Trustees, who overturned the jury's decision. The prize went, instead, to Edith Wharton for The Age of Innocence. In 1926 Lewis refused the Pulitzer when he was awarded it for Arrowsmith.
In 1930, Lewis was the first American ever awarded the Nobel Prize for Literature. While a Nobel Prize is awarded to the author not the work, and itself does not cite a particular work for which he was chosen, Main Street was Lewis' best-known work and enormously popular at the time. In the Nobel committee's presentation speech, both Main Street and Arrowsmith were cited. The prize was awarded "...for his vigorous and graphic art of description and his ability to create, with wit and humour, new types of characters."
In 1998, the Modern Library ranked Main Street #68 on its list of the 100 best English-language novels of the 20th century.