Dorothea Brooke is an idealistic, well-to-do young woman, engaged in schemes to help the lot of the local poor. She is seemingly set for a comfortable, idle life as the wife of neighboring landowner Sir James Chettam, but to the dismay of her sister, Celia (who later marries Chettam), and of her loquacious uncle Mr. Brooke, she marries instead Edward Casaubon, a middle-aged pedantic scholar who, she believes, is engaged on a great work, The Key to All Mythologies. She wishes to find fulfillment through sharing her husband’s intellectual life, but during an unhappy honeymoon in Rome she experiences his coldness towards her ambitions. Slowly she realizes that his great project is doomed to failure and her feelings for him descend to pity. She forms a warm friendship with a young cousin of Casaubon’s, Will Ladislaw, but her husband’s antipathy towards him is clear (partly based on his belief that Ladislaw is trying to seduce Dorothea in order to gain access to Casaubon's fortune) and Ladislaw is forbidden to visit. In poor health, Casaubon attempts to extract from Dorothea a promise that, should he die, she will "avoid doing what I should deprecate and apply yourself to do what I desire" — meaning either that she should shun Ladislaw, or, as Dorothea believes, that she will complete The Key to All Mythologies in his place. Before Dorothea can give her reply, Casaubon dies. She then learns that he has added the extraordinary provision to his will that, if she should marry Ladislaw, Dorothea will lose her inheritance from Casaubon.
Meanwhile, an idealistic young doctor, Tertius Lydgate, has arrived in Middlemarch, with advanced ideas for medical reform. His voluntary hospital work brings him into contact with the town’s financier, Mr. Bulstrode, who has philanthropic leanings, but who is also a religious zealot with a secret past. Bulstrode’s niece is Rosamond Vincy, the mayor’s daughter and the town’s recognized beauty, who sets her sights on Lydgate, attracted by what she believes to be his aristocratic connections and his novelty. She ensnares him, but the disjunction between her self-centeredness and his idealism ensures that their marriage is unhappy. Through a combination of her material greed and Lydgate’s weakness he is soon deep in debt and has to seek help from Bulstrode. He is partly sustained emotionally in his marital and financial woes by his friendship with Camden Farebrother, the generous-spirited and engaging parson from a local parish.
At the same time we have become acquainted with Rosamond’s university-educated, restless, and somewhat irresponsible brother, Fred, reluctantly destined for the Church. He is in love with his childhood sweetheart, Mary Garth, a sensible and forthright young woman, who will not accept him until he abandons the Church (which she knows he has no interest in) and settles in a more suitable career. Mary has been the unwitting cause of Fred’s loss of a considerable fortune, bequeathed to him by the aged and irascible Mr. Featherstone, then rescinded by a later will which Featherstone, on his death-bed, begs Mary to destroy. Mary, unaware of what is at stake, refuses to do so. Fred, in trouble over some injudicious horse-dealing, is forced to borrow from Mary’s father, Caleb Garth, to meet his commitments. This humiliation shocks Fred into a reassessment of his life and he resolves to train as a land agent under the forgiving Caleb.
Includes a biography of the author