Some of Lewis's contemporaries said the novel was too bleak, even humorless, in its conveyance of ignorant small-town life and people. However, Main Street is generally considered to be Lewis's most significant and enduring work, along with its 1922 successor Babbitt.
Some small-town residents resented their portrayal and the book was banned by the public library of Alexandria, Minnesota.
Because of the popularity acquired by Lewis and his book, high-school teams from his hometown of Sauk Centre, Minnesota, began to be called the Main Streeters as early as the 1925–26 school year. This name was essentially given to the town by the nearby towns at school events. The Sauk Centre High School still goes by the name in a tribute to Lewis.