Synopsis 
The central story, with which the novel opens, is that of Dorothea Brooke, a beautiful and idealistic young woman who is frustrated by what she sees as the selfish concerns of those around her, and who longs to find some great purpose for her life and to help others. To the horror of her uncle and sister Celia, she refuses marriage with the good-natured but less imaginative young land-owner, Sir James Chettam, choosing instead Mr Casaubon, a scholarly clergyman in late middle-age. Dorothea believes that Casaubon will teach her and engage her in helping with his 'great work'. However, after their marriage she finds that that Casaubon rejects her attempts to help, and resents her youthful energy and enthusiasm, and she begins to realise that his 'great work' will in the end amount to nothing. His neglect throws her into the company of his poor cousin, Will Ladislaw, young and ambitious like herself, but lacking any settled purpose. Will's growing admiration for Dorothea drives him to leave and immerse himself in working to establish a career. After Casaubon dies suddenly, Dorothea discovers that he has made a codicil in his will stating that she will forfeit her inheritance if she marries Will. Although Dorothea uses some of the money for charitable work, her final choice is to give up wealth in favour of happiness with Will, who becomes deeply engaged in the struggle for political reform.
Interwoven with Dorothea's story is that of Tertius Lydgate, a young and ambitious doctor who arrives in Middlemarch with plans to build a new hospital, and dreams of making advances in medicine while helping the poor in a small community where he can become closely acquainted with his patients. Lydgate falls in love with the pretty but vain and selfish Rosamund Vincy, and against his better judgement marries her. Unable to refuse her demands, Lydgate falls into debt to the disreputable but outwardly pious banker Bulstrode. This indebtedness forces him into a compromising position, and when Bulstrode's past is exposed, Lydgate's close connections with him prove his downfall. Dorothea, who has stepped in to provide funding for the New Hospital, is one of the few to believe in Lydgate's innocence. He is forced to leave Middlemarch and become a doctor in London, abandoning his idealistic ambitions and catering instead to wealthy and lucrative clients.
One of the main sub-plots follows the fortunes of Rosamund's brother Fred, a good-hearted but rather dissolute young man who is studying rather half-heartedly to become a clergyman, and living in expectation of inheriting the fortune of his uncle Mr Featherstone. He is in love with Mary Garth, a poor but kind and practical young woman who works as Mr Featherstone's nurse. She refuses to marry Fred until he can give up his gambling, and devote himself to a profession more suited to him. Fred has persuaded Mary's father to stand as security for his debts, believing he will soon be able to pay them off, but when he does not receive his expected inheritance, Mr Garth is forced to pay on his behalf. This finally pushes Fred to realise that he must turn his life around, and he becomes an apprentice to Mr Garth, and finally succeeds in winning Mary's hand.