Dorothea is an earnest intelligent woman who makes a serious error in judgment when she chooses to marry Edward Casaubon, a pompous scholar many years her senior. Dorothea hopes to be actively involved in his work, but he wants her to serve as a secretary. She comes to doubt both his talent and his alleged magnum opus. Furthermore, the controlling Casaubon becomes jealous when she develops a friendship with Will Ladislaw, his idealistic cousin. Although disappointed, Dorothea remains committed to the marriage and tries to appease her husband. After Casaubon has a heart attack, Dorothea is clearly devoted to him, but he bars Ladislaw from visiting, believing that his cousin will pursue Dorothea when he dies. Casaubon subsequently seeks her promise that she will follow his wishes even after his death. She delays answering but ultimately decides that she should agree to his request. However, he dies before she can tell him. Dorothea later discovers that his will contains a provision that calls for her to be disinherited if she marries Ladislaw. Afraid of scandal, Dorothea and Ladislaw initially stay apart. However, they ultimately fall in love and marry. Ladislaw later becomes a politician, and, despite her sacrifices, Dorothea is content, because “the growing good of the world is partly dependent on unhistoric acts.”
During this time, Lydgate’s story unfolds. He is a progressive young doctor who is passionate about medicine, especially his research. Soon after arriving in Middlemarch, he becomes involved with and later marries Rosamond Vincy, whom he finds to be “polished, refined, [and] docile,” all qualities he wants in a wife. For her part, Rosamond believes that marriage to Lydgate, who she does not realize is poor, will improve her social standing.. Lydgate comes to realize that he has made a mistake in choosing Rosamond. She is shallow and uninterested in his work, and her expensive lifestyle forces her husband to the brink of financial ruin. He seeks a loan from Nicholas Bulstrode, a widely disliked banker, but is refused.
Bulstrode is not without his own problems. He is being blackmailed by John Raffles, who knows about Bulstrode’s unsavoury past. When Raffles becomes ill, Bulstrode tends to him and sends for Lydgate. During one of the doctor’s visits, Bulstrode offers to lend Lydgate the money he had previously refused, and Lydgate accepts. Bulstrode subsequently disregards Lydgate’s medical instructions, causing Raffles to die. When the true story about Bulstrode and Raffles comes to light, questions arise over Lydgate’s possible involvement in the latter’s death. One of the few people who believes his innocence is Dorothea, and he is taken by her compassion and kindness. Lydgate and Rosamond are ultimately forced to leave Middlemarch, and they move to London, where Lydgate becomes wealthy but considers himself a failure. He ultimately dies at age 50.