Arkady Nikolaevich returns to his father's farm at Maryino on the 20th of May 1859. His father, Nikolai, is ecstatic to see him, and happily takes in Bazarov, Arkady's new friend from school in Petersburg.
Nikolai is a widower who has recently freed his serfs (members of the Russian peasant class, bound to a landowning lord), and he has been selling off his land to make ends meet. He has a relationship with a young girl named Fenichka who used to be a servant, and the two of them now have a son named Mitya. He lives with his brother, Pavel, who used to be a great general.
One morning when Bazarov goes out to collect frogs (he enjoys doing experiments on them), Pavel and Nikolai ask Arkady about his new friend. Arkady proudly tells them that Bazarov is a nihilist, a man willing to question every principle no matter how much it is revered. The two old men are a bit taken aback, and, when Bazarov returns, he and Pavel have an argument. Pavel is much prouder than his brother Nikolai, and he has no patience for the rude young man.
Arkady, though still loyal to his friend, notices how rude Bazarov is. He tried to get him to sympathize with Pavel by telling him Pavel's story. Pavel was a well-respected society man and a captain in the army, but then he lost his head over an enigmatic woman named Princess R. She never accepted his advances, and eventually died in a state of insanity. Bazarov persists in his arrogance, and thinks that Pavel has made a mess of his own life and now preaches to the young.
A few weeks later, an even larger fight erupts between Pavel and Bazarov. Pavel argues that one cannot live without principles, and that the Russians are a traditional people, a people of faith. Bazarov, for his part, argues that the young can do nothing more useful than renounce everything. Both men lose their tempers, and separate in order to cool off. After observing the argument, Nikolai remembers a time he told his mother that she couldn't understand him because she was of a different generation. He wonders if the same thing has now happened between himself and his son Arkady.
Bazarov and Arkady go to a nearby town to visit a successful relative of Arkady's, Matvei Ilyich Kolyazin. Kolyazin takes Arkady under his wing and invites the two young men to a ball. The same day, Bazarov runs into an old companion named Victor Sitnikov, who insists that they come and have drinks with a clever older woman he has met, Madame Kukshin. Madame Kukshin tries hard to draw Bazarov out, but he is unimpressed and reveals that he has little interest in women's rights – a subject about which she is very passionate.
At the ball, Arkady and Bazarov meet Anna Sergeyevna Odintsov, an acquaintance of Madame Kukshin's. Arkady is instantly smitten with her, and manages to chat with her for most of the night. It is clear, however, that she is more curious about Bazarov. She invites the two of them to her hotel, and then to her place in the country at Nikolskoye.
Anna Sergeyevna grew up very independent. Her father lost his fortune gambling and died young. She and her sister Katya would have had a simple life if she hadn't met Monsieur Odintsov. Anna and Odintsov were married, and, when he died, he left them a fortune.
Over the course of the visit, she and Bazarov become very close. Arkady feels like he is elbowed out, and he is left to spend most of his time with Anna's younger sister, Katya. Though Bazarov can hardly admit it to himself, he is falling in love with Anna Sergeyevna. For her part, she reveals to him that she feels incomplete, that she worries that happiness will elude her. Bazarov is frustrated with her and thinks she is being coy, but he can't help himself. He makes a declaration of love to her, and she rejects him.
The situation at Nikolskoye becomes very tense until Sitnikov arrives, uninvited. Shortly after, Bazarov decides that he will go to visit his parents, who have been dying to see him. Arkady announces that he will also leave, but opts to go to Bazarov's home over riding back to Maryino with Sitnikov. In the carriage, Bazarov tells Arkady that they both acted like fools; that they were too taken in by the women at Nikolskoye. He tells himself that he is over Anna Sergeyevna, and looks forward to seeing his father.
Bazarov's parents, Vassily Ivanych and Arina Vlassyevna, are thrilled to see him. It has been three years, and they clear out a room for him and Arkady and do their best not to fuss over them. Arkady has a talk with Vassily Ivanych about Bazarov, and they both agree that one day he will be a great man. Bazarov, however, seems irritated by his parents. He is in a dark and melancholy mood, and when Arkady comments on his cynicism, the two of them begin to bicker. After just three days, Bazarov decides to leave, though he promises his parents he will return soon. They are crushed, and cling to one another in their grief.
On the way home, Arkady talks Bazarov into making a detour to the Odintsovs'. It is a brief and awkward visit, but Anna Sergeyevna encourages them to stop back at another time. When they return to Maryino, Arkady realizes that he can't stop thinking of the Odintsovs. His father shows him some letters that Anna Sergeyevna's mother sent to Arkady's mother, and Arkady decides to use it as a pretext to return. When he does, Anna Sergeyevna is very happy to see him, but he realizes that it is Katya he can't stop thinking about.
Bazarov is left alone at Maryino, and retires into solitude, working all day. Pavel tolerates him, and Nikolai enjoys popping in to help with experiments. Bazarov begins to become close with Fenichka. One day, the two of them are joking around and he makes a move and kisses her. A moment later, Pavel emerges from behind a nearby bush. Fenichka is embarrassed and angry with Bazarov.
Pavel does not tell his brother what happened. The next day, however, he proposes a duel to Bazarov. Bazarov takes it all as tongue-in-cheek, but agrees. They meet in the morning using the servant Piotr as witness. Pavel fires first and misses, and Bazarov shoots and hits Pavel in the thigh. As soon as Pavel is hit, Bazarov goes and attends to him. Piotr rushes back to get Nikolai. Bazarov and Pavel lie to him and say they fell out over English politics. Bazarov leaves as quickly as he can, and, as Pavel heals, he tells Nikolai that he wants him to do right by Fenichka and marry her. Nikolai is thrilled since the only reason he hadn't already done so was because he was afraid that Pavel would disapprove.
Meanwhile, Arkady is spending a great deal of time with Katya at Nikolskoye. They discuss Bazarov and Anna Sergeyevna, and Katya thinks that Arkady is coming out from under the shadow of Bazarov's influence. Bazarov comes to Nikolskoye to tell Arkady what happened with Pavel. Arkady is shocked, but Bazarov assures him that Pavel is fine. At Arkady's insistence, Bazarov goes to see Anna Sergeyevna.
The two of them are uncomfortable together, though they fall into a companionable relationship. Bazarov reveals to Anna Sergeyevna that Arkady was in love with her when they first met, and she begins to think differently of Arkady. The next day, however, Arkady asks Katya to meet him out on the portico. He tries to propose, but trips over his words. They are interrupted when they overhear a conversation between Bazarov and Anna Sergeyevna, who are walking nearby.
It comes out that Anna Sergeyevna is considering a relationship with Arkady, but as soon as she and Bazarov walk on, Arkady proposes to Katya. She accepts and he is thrilled. Bazarov decides that he must leave and return home. He tells Arkady that this is their last goodbye, and that Arkady lacks the spirit that he himself has. He thinks that gentry will only go so far, they will not fight. Arkady is disappointed that Bazarov doesn't have anything nicer to say to him at their parting, but, when he begins speaking with Katya after Bazarov departs, Arkady quickly forgets him.
Bazarov returns home, and begins helping his father, a doctor, treat the local peasants. Vassily Ivanych is happy and very proud, but he worries that Bazarov is sad and gloomy. One day, Bazarov is in town, and decides to help the local doctors open up a man who recently died of typhus. In the process, he accidentally cuts himself. He is very calm about it, but as the days pass, it becomes clear that he has contracted the disease. He is feverish and bed-ridden.
One of Bazarov's last wishes is for his father to send a message Anna Sergeyevna and tell her that he is dying. His father does so, and Anna Sergeyevna immediately comes to see them with a German doctor in tow. Bazarov is partly delirious. He thinks ironically of all the time he spent considering himself a giant, and now his only problem is how to die decently. At his request, Anna Sergeyevna gives him a kiss on the forehead before she leaves. He dies the same evening.
The book closes with the weddings of Nikolai and Fenichka and Arkady and Katya. Pavel leaves them and goes to Dresden to live out the remainder of his life. The narrator surveys the lives of all the characters before ending by speaking of Bazarov's grave. Bazarov's parents often go there to pray and weep, and the narrator thinks that no matter how stubborn their son was in his nihilism, it is not possible that they weep in vain.