The novel starts with Severus Snape meeting with Narcissa Malfoy, who expresses concern that his son Draco might not survive a dangerous mission given to him by Voldemort. He makes an Unbreakable Vow with her to protect and assist Draco in his mission.
Dumbledore takes Harry to former Potion teacher, Horace Slughorn home and persuades him to return to Hogwarts. He then takes Harry to the Burrow, where Hermione was already staying. The next morning they receive their O.W.L. results and their school supply list. Later, Ron and Hermione follow Draco to a Dark Arts store. Harry begins to believe that Draco is a Death Eater.
The students return to Hogwarts and Dumbledore informs them that Professor Snape will be teaching Defence Against the Dark Arts and Slughorn will continue to teach Potions. With the aid of a used textbook meticulously annotated by the mysterious "Half-Blood Prince," Harry becomes the top student in his Potions class. The Prince's tips helped Harry win a bottle of Felix Felicis or Liquid Luck. Harry’s superiority in potions angers Hermione.
Dumbledore and Harry have regular meetings in which they use the Pensieve to experience memories relating to Voldemort's childhood. Dumbledore slowly reveals that Voldemort has split his soul into seven parts, hiding six of them (one still being inside Voldemort) in magical containers known as horcruxes. While a part of his soul still exists, Voldemort cannot be killed. This explains why Voldemoret lived after failing to kill Harry at Godrics Hollow.
During the year, Ron begins to date Lavender Brown (very publicly, like seriously over the top PDA) in order to make Hermione jealous for kissing Viktor Krum. They later reconcile after Ron is nearly killed in an attempt on Dumbledore’s life. Ron and Lavender break up after she sees both of them walking out of the girl’s dormitories together. Meanwhile, Harry develops a crush on Ginny, but is reluctant to date her because of his friendship with Ron. Eventually, Ron finds out and gives Harry his blessing.
Harry and Dumbledore traveled to a cave in order to retrieve Slytherin’s locket, one of the seven horcrux. In order to access the locket, Dumbledore must drink a vile potion. In a flurry of events, Dumbledore finishes the potion. He is seemingly incoherent, bailing and crying out for water. Harry tries to get him water, but touching the lake water triggers an inferi (reanimated human corpses) attack. Dumbledore comes to the rescue at the last minute, and, locket in tow, the duo escape to Hogsmeade. When they arrive, Dumbledore learns that the Dark Mark had been placed over Hogwarts while he was away. At the tallest tower, Dumbledore hides Harry with the Cloak of Invisibility and uses the Freezing Charm on him. Draco arrives with a troop of Death Eaters whom he helped access the castle. Draco disarms Dumbledore and then threatens to kill him-- the mission Voldemort gave him that is referenced in Chapter 1. Dumbledore stalls Draco until Severus Snape arrives. Dumbledore pleads with him, "Severus, please." Snape does not hesitate. He kills Dumbledore with the Avada Kedavra curse. Dumbledore, lifeless, tumbles off of the tower.
Dumbledore's spell is broken the moment he dies, and Harry rushes after Snape in an attempt to avenge the murder of his Headmaster. Snape escapes, but not before revealing that he is the Half-Blood Prince. Later, Harry is appalled to learn that the locket was not a real horcrux, but a copy created by someone named R.A.B., who has the real horcrux.
In the fighting on the night of Dumbledore's death, Ron's brother, Bill, was attacked and bitten by Fenrir Greyback, a notorius werewolf who also bit Remus Lupin. It is unclear whether Bill we become a werewolf, but the damage to his person is permanent. His fiancée, Fleur Delacour, insists that she will still marry Bill.
After Dumbledore’s funeral, Harry breaks up with Ginny, saying that’s it’s dangerous for them to be dating. Harry tells Ron and Hermione that he is not returning to Hogwarts next year, but instead he will be hunting the remaining horcruxes. His loyal friends are determined to join him.