Spanning a period of 10 to 15 years, the story details the lives of Tom and Maggie Tulliver, siblings growing up at Dorlcote Mill on the River Floss. The narrative follows Maggie's relationship with her older brother Tom, and her romantic relationships with Philip Wakem (a hunchbacked, sensitive and intellectual friend) and with Stephen Guest (a vivacious young socialite).

The Mill on the Floss articulates the tension between circumstances and the spiritual energies of individual characters struggling against those circumstances. Critics have asserted that Maggie's need for love and acceptance is her underlying motivation throughout The Mill on the Floss, claiming that the conflicts that arise in the novel invariably stem from her frustrated attempts at gaining this acceptance.