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 informs them that Snape will be teaching Defence Against the Dark Arts and Slughorn will continue to teach Potions. Harry is the top student in Potions class, using a used textbook with annotations that was owned by “The Half-Blood Prince.” His tips helped Harry win a bottle of Felix Felicis or Liquid Luck. Harry’s intelligence in potions angers Hermione.
Dumbledore regularly reunites with Harry; in which they use his Pensieve to look at memories relating to Voldemort. Using his Liquid Luck, Harry retrieves on of Slughorn’s memory about how he revealed to Voldemort about creating a horcrux, which would grant him immortality. Dumbledore tells Harry that in order to make Voldemort mortal, all of the horcrux must be destroyed.
During the year, Ron begins to date Lavender Brown 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 falls in love with Ginny, but is reluctant to date her because of his friendship with Ron. He starts dating Ginny, after Ron gave him his blessing.
Harry and Dumbledore traveled to a cave in order to retrieve Slytherin’s locket, one of the seven horcrux. Dumbledore drinks a potion, in order to obtain the locket. The potion weakens him and Voldemort’s Inferi began attacking them. They retrieve the locket and returns to Hogwarts. When they arrive, Dumbledore learns that the Dark Mark had been placed in Hogwarts, while he was away. Dumbledore hides Harry with the Cloak of Invisibility and uses the Freezing Charm on him. Draco arrives, next to Death Eaters, he helped get inside of Hogwarts. Draco disarms Dumbledore’s wand and then threatens to kill him, a mission Voldemort gave him. Dumbledore tried to stall Draco, who is unable to kill him, but Snape arrives and kills him.
Harry’s spell is broken because of Dumbledore’s death and he rushes after Snape to avenge his death. Snape reveals that he is the Half-Blood Prince and escapes. Later, Harry learns that the locket was not a real horcrux, but it contained a note by someone named R.A.B.
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 for the remaining horcruxes. Ron and Hermione joined him in order to destroy Lord Voldemort.