Dorothea Brooke is a highly intelligent, very religious young woman from a “good family.” She and her sister Celia are orphans and live under the care of their unmarried uncle, Mr. Brooke, in Tipton Grange. Sir James Chettam is courting Dorothea, and comes to dinner at Tipton along with Rev. Edward Casaubon, a 45-year-old bachelor and theological scholar. Casaubon has spent multiple decades working on an ambitious work of religious history, The Key to All Mythologies.
Dorothea has been passionately at work on architectural designs for cottages for the tenant farmworkers in Tipton. At dinner, she takes a liking to Casaubon, whom she believes resembles John Locke and must be a “great man.” She fantasizes that he will propose to her and imagines a life wherein she can fulfil her intellectual ambitions through helping him finish The Key to All Mythologies. Sir James is enthusiastic about seeing Dorothea’s plans for the cottages come to fruition, whereas Casaubon seems uninterested in them.
Mr. Brooke tells Dorothea that Casaubon is interested in marrying; soon after, Casaubon sends Dorothea a rather stiff, awkward letter in which he proposes to her. Dorothea is so happy that she bursts into tears and drops to the floor. Mr. Brooke and their family friend Mrs. Cadwallader are both hesitant about the idea of Dorothea accepting Casaubon, but they eventually relent, saying that Dorothea can do what she wants. Sir James is also shocked and horrified at Dorothea’s decision, but more out of concern for her than pity for himself. He and Dorothea remain friends and he continues to make regular visits to Tipton.
While on a premarital visit to Casaubon’s house Lowick Manor, Dorothea, Celia, Mr. Brooke, and Casaubon run into Casaubon’s second cousin, Will Ladislaw, who is carrying a sketchbook. Later, a dinner party is held at Tipton in advance of the wedding. The attendees include Tertius Lydgate, an ambitious young doctor who has just moved to Middlemarch and hopes to bring cutting-edge medical reform to the area. Lydgate has become entranced by Rosamond Vincy, who is known as the most beautiful young woman in Middlemarch. Rosamond’s brother Fred is a lazy, irresponsible, and arrogant young man.
Fred expects to inherit the land of his uncle Mr. Featherstone, an ailing and widely disliked yet very wealthy individual. Fred has been using this anticipated fact to borrow money. Fred is in love with Mary Garth, whom he has known since they were children. Rosamond, meanwhile, is determined to marry Lydgate, believing that she can rise in wealth and status by doing so.
Bulstrode is a wealthy banker who is treated with suspicion because he is a newcomer of obscure origins, and also because he is evangelical. He is financing the New Hospital and asks Lydgate to serve as director. Although Fred originally borrowed money for gambling from the local horse-dealer Mr. Bambridge, after he couldn’t pay it, Caleb Garth co-signed for him.
When Lydgate was living in Paris he fell in love with an actress who named Laure who killed her husband onstage. The incident left Lydgate determined to maintain a “scientific” attitude toward women from then on. He is very charmed by Rosamond, but doesn’t want to marry for another five years as he first needs time to focus on his career. Lydgate develops a friendship with a vicar named Farebrother, and Lydgate feels reluctant about voting for Mr. Tyke for the chaplaincy at the New Hospital. However, Lydgate eventually gives in to pressure from Bulstrode and gives the deciding vote to Tyke.
While at the Vatican, Will Ladislaw and his friend Adolf Naumann, a German painter, catch sight of Dorothea. Dorothea is not enjoying her honeymoon; she feels disappointed by Casaubon’s behavior toward her and particularly his refusal to let her help him with his scholarly work. Will comes to see her at her apartment while Casaubon is working at the Vatican library; when Casaubon finds out, he wants to ban Dorothea from seeing Will alone, but he doesn’t go through with it. The next day, Naumann asks both Dorothea and Casaubon to sit for him and they agree. Will visits Dorothea alone again and reveals that The Key to All Mythologies is doomed to failure because Casaubon can’t read German and thus doesn’t know the latest developments in theological scholarship.
Fred remains troubled by his debt and at the same time fails his university exam, which makes him feel even worse. He attempts to make some money through the sale of a horse, but the horse lames itself and Fred ends up in a worse position than he was to begin with. Miserable, he confesses to Caleb that he can’t come up with the money. Caleb and Mrs. Garth realize that they will have to give up their savings, which they’d been hoping to use to pay for their son Alfred’s apprenticeship. They will also have to ask Mary for some of her savings.
Fred develops a fever; the Vincys’ doctor Mr. Wrench tends to him but Fred’s condition only deteriorates. Rosamond sees Lydgate walking past and calls him in. Lydgate observes that Wrench gave Fred the wrong medicine and diagnoses him with typhoid fever. Mrs. Vincy joyfully declares that Lydgate has saved Fred’s life. Dorothea returns from her honeymoon to the news that Celia and Sir James are engaged. Casaubon is ill, and when Lydgate checks up on him he says that Casaubon has a heart condition that could prove fatal if he doesn’t stop working so much.
Mrs. Bulstrode hears a rumor that Lydgate and Rosamond are engaged, and after she asks Lydgate about it he resolves to stop coming to the Vincys’ house unless for professional reasons. Rosamond is distraught; once Lydgate sees how miserable she is, he realizes he loves her and proposes.
As Mr. Featherstone’s death draws near, his relatives crowd around his house, hoping to ensure their inheritance. He is annoyed and tells them that he’s already made his will. Mary is working as his caregiver; one night he wakes in the middle of the night and requests that she burn one of the two wills he has made. She refuses, knowing that this will make people suspicious of her. He tries to bribe her with £200 but she remains adamant. Shortly afterward, Featherstone dies.
At the reading of Mr. Featherstone’s will, it is revealed that all of his money and land will go to his illegitimate son, Joshua Rigg, whom no one in Middlemarch has ever seen before. The relatives are furious and the Vincys are especially distraught. Mr. Vincy tries to rescind his approval of Rosamond and Lydgate’s engagement as Lydgate does not have enough money.
England is gripped by political tumult as the possibility of electoral reform gains momentum. Mr. Brooke buys the local progressive newspaper, The Pioneer, and employs Will Ladislaw as editor-in-chief. Casaubon tries to stop this happening, as he is increasingly suspicious of Will’s attachment to Dorothea. However, Will defies him and accepts the position. Meanwhile, Brooke is accused of being a hypocrite for running for election on a progressive platform while he is known to be an unkind landlord.
Mr. Brooke hires Caleb to manage Freshitt (Sir James’s property) and Tipton, which saves the Garths from financial ruin. Fred has returned from university where he was finally able to pass his exam and obtain his degree. However, he doesn’t want to enter the church.
Joshua Rigg’s stepfather John Raffles arrives in Middlemarch, seeking money from Rigg. Rigg bitterly dismisses him due to the fact that Raffles is an alcoholic who used to beat Rigg. Meanwhile, Lydgate (who has just returned from his honeymoon) discusses medical reform with Dorothea, who pledges to give £200 a year to the New Hospital. Despite this success, Lydgate continues to face opposition from most people in Middlemarch. Will and Lydgate become friends, and Will frequently spends time at Rosamond and Lydgate’s house.
Casaubon, whose health continues to fail, asks Dorothea to make a promise to him that she will fulfil a request of his after he dies. Thinking that he intends to ask her to finish The Key to All Mythologies, Dorothea hesitates and says she will give him an answer in the morning. She decides to say yes, but when she goes to tell Casaubon her answer, she finds him dead. Mr. Brooke and Sir James learn that a stipulation in Casaubon’s will states that if Dorothea marries Ladislaw she will lose all her property. Celia reveals this to Dorothea, who is shocked. For the first time she consciously considers the possibility that she has feelings for Will.
Mr. Brooke gives a speech as part of his election campaign and is pelted with eggs. Fred enlists Farebrother to help him find out if Mary would approve of him becoming a clergyman; she tells Farebrother that she will never marry Fred if he enters the church. Raffles returns to Middlemarch and this time begins harassing Bulstrode. It becomes clear that Raffles knows secrets about Bulstrode’s past that he is hoping to use to blackmail him, and that these secrets somehow involve Will.
Following Casaubon’s death, Dorothea has been living in Freshitt with Celia and her new baby, but she is growing bored. Will visits her and tells her he is leaving Middlemarch. While Caleb and his assistant Tom are surveying land in preparation for the construction of a railway, they are attacked by a mob of farmworkers who are opposed to the railway. Fred helps defend Caleb and Tom, and Caleb offers Fred a job as a kind of apprentice. Mr. Vincy is miserable about this development, as it means Fred’s education was a waste of money.
Rosamond has a miscarriage after horseback riding when Lydgate told her not to. She and Lydgate are deeply in debt, forcing Lydgate to sell their silverware, which infuriates Rosamond. Rosamond tells Will about the stipulation in Casaubon’s will forbidding him from marrying Dorothea.
Raffles’s presence continues to trouble Bulstrode. When Bulstrode was young he befriended a man from his church named Mr. Dunkirk, who ran a pawnbroking business. Bulstrode worked as the accountant for the business, which pawned stolen goods. After Mr. Dunkirk died Bulstrode married his widow. The widow wanted to find her estranged daughter, Sarah (who was Will’s mother), in order to give Sarah her inheritance. Bulstrode bribed Raffles to pretend that Sarah couldn’t be found so that Bulstrode could inherit the money himself.
Back in the present, Bulstrode tries to give Will the inheritance as a form of atonement, but Will refuses to take it. Will goes to say goodbye to Dorothea again, and this time she realizes that he loves her. He leaves Middlemarch for real this time. Lydgate is now £1000 in debt and attempts to sell his house to Ned Plymdale; however, Rosamond secretly stops the sale from happening. In desperation, Lydgate asks Bulstrode for money. Bulstrode refuses and advises Lydgate to file for bankruptcy; he also says that Lydgate will need to step back from running the New Hospital.
Raffles reappears, seemingly very sick. Bulstrode takes him in and calls Lydgate, who diagnoses Bulstrode with alcohol poisoning. Changing his mind, Bulstrode gives Lydgate the £1000 he needs. Bulstrode neglects to tell the servant caring for Raffles the proper instructions for his care, and Raffles dies. However, Raffles had already told Bambridge. the local horse dealer, the secret story of Bulstrode’s past and the gossip spreads around Middlemarch like wildfire. Bulstrode is thought to have bribed Lydgate to help him kill Raffles. The scandal has a catastrophic effect on both of them, forcing them to prepare to leave Middlemarch, abandoning the New Hospital.
Dorothea says that she believes Lydgate is innocent and tries to get him to stay, but Lydgate refuses. She also writes him a check for £1000 so he is no longer in debt to Bulstrode. Dorothea goes to the Lydgates’ and sees Will and Rosamond holding hands while Rosamond cries; she misinterprets this sight as evidence that Will and Rosamond are in love. Later, Dorothea comes to see Rosamond and Rosamond explains the misunderstanding, adding that Will loves Dorothea.
Will and Dorothea finally admit their feelings to one another, although Will initially remains convinced that they cannot marry due to Casaubon’s will. Dorothea tells him that she will forsake her fortune to marry him, despite the fact that most of her close friends and family members are against the union. Bulstrode leaves Middlemarch, agreeing to give his house to Fred.
In the “Finale,” the narrator explains what happens to each of the main characters after the end of the main narrative. Fred and Mary get married and have a happy, prosperous life together. Rosamond and Lydgate’s marriage remains unhappy and when Lydgate dies at 50, he considers himself a failure. Dorothea and Will live in London, where Will has a successful political career and Dorothea is a wife and mother.