Main Street is the story of Carol Clifford, a progressive city girl who marries the pleasant small-town doctor Will Kennicott. The two return to Will's hometown of Gopher Prairie, but the idyllic small town environment proves stupefying and frustrating for Carol. She fights against the town's backwardness and conservative views, but backbiting and a vicious series of cliques within the town make it very hard for her to live happily. Carol flees to Washington D. C. , returning only later and without intent to fight further.
Carol Milford is a liberal, free-spirited young woman, reared in Saint Paul, Minnesota, the state capital. She marries Will Kennicott, a doctor, who is a small-town boy at heart.
When they marry, Will convinces her to live in his home-town of Gopher Prairie, Minnesota (a town modeled on Sauk Centre, Minnesota, the author's birthplace). Carol is appalled at the backwardness of Gopher Prairie. But her disdain for the town's physical ugliness and smug conservatism compels her to reform it.
She speaks with its members about progressive changes, joins women's clubs, distributes literature, and holds parties to liven up Gopher Prairie's inhabitants. Despite her friendly but ineffective efforts, she is constantly derided by the leading cliques. Carol finds comfort and companionship outside her social class. These companions are taken from her one by one.
In her unhappiness, Carol leaves her husband and moves for a time to Washington, D.C., but she eventually returns. Nevertheless, Carol does not feel defeated. She states, "I do not admit that Main Street is as beautiful as it should be! I do not admit that Gopher Prairie is greater or more generous than Europe! I do not admit that dish-washing is enough to satisfy all women! I may not have fought the good fight, but I have kept the faith."