Lord Voldemort has returned to power, and his wrath has been felt in both the Muggle and Wizarding worlds. Severus Snape, long considered an enemy of Voldemort and a member of Dumbledore's anti-Voldemort coalition, the Order of the Phoenix, meets with Narcissa Malfoy, mother of Draco and wife of Lucius, an imprisoned death eater. Snape makes an Unbreakable Vow to Narcissa, promising to protect her son, Draco.
Dumbledore heads to 4 Privet Drive to collect Harry from his aunt and uncle. On their way to the Burrow, Harry and Dumbledore stop to recruit Horace Slughorn to return to teaching at Hogwarts. Harry is reunited with his best friends, Ron and Hermione. When shopping for school books, Harry runs into Draco Malfoy, and his child hood friend, Alyssa Prewett, whom is Ron's cousin. Ron, however, is oblivious to this. Harry follows Draco and Alyssa to Borgin and Burkes, where the two teens are over heard threatening Borgin and insisting that he fix an unknown object. Harry is instantly suspicious of Draco and Alyssa, whom he believes to be death eaters like his father and her mother. The students return to school and Dumbledore announces that Snape will be teaching Defense Against the Dark Arts, much to Harry's surprise.
Harry receives a used Potions textbook that once belonged to someone named "The Half-Blood Prince." Spells and amendments are written in the margins of the text book, and Harry uses the Prince's notes to excel at Potions. Dumbledore schedules regular meetings with Harry in which they use Dumbledore's pensive to look at memories of those who had direct contact with Voldemort. Dumbledore believes that if Harry can learn enough about Voldemort's history, it will help him when they fight face to face, as the prophecy concerning Harry foretells. Harry learns about Voldemort's family, including his grandfather Marvolo, his uncle Morfin, and his mother Merope who cast a love spell on a Muggle and was abandoned when the spell wore off. Voldemort was left at an orphanage and grew to be an unpleasant and aggressive boy. Harry also learns that Voldemort has divided his soul into seven Horcruxes. Two of these, Tom Riddle's diary and Marvolo's ring, have already been destroyed. One resides in Voldemort, one resides in a snake, one is Merope's locket and the other two are suspected to be hidden in objects belonging to Hufflepuff, Ravenclaw, or Gryffindor.
Ron acquires a new girlfriend, Lavender, of whom Hermione is extremely jealous. Harry feels stuck in the middle of his friends' bickering. Eventually, Harry falls in love with Ginny, Ron's sister, and Ron and Lavender break up, making Hermione quite happy. Harry spends much of his time keeping up with his duties as Quidditch captain and following Draco Malfoy and Alyssa Prewett, who are boyfriend and girlfriend. Harry uses his Marauder's map to keep track of the couple, mainly Draco, but he often cannot find them on the map. Eventually, Harry realizes that when they are not on the map, Draco and Alyssa are using the Room of Requirement on the seventh floor of Hogwarts, which transforms into whatever its user needs. Harry tries his best to get in and see what the couple is up to, but until he knows exactly what they are using it for, he cannot gain access.
Meanwhile, Piper Ashby prepares for a big grand exit from Hogwarts. She is a seventh year, whom is dating George Weasley, one of Ron's twin older brothers. She hangs out with others in her Ravenclaw house who help prepare the grand exit. Eventually, Piper has a run in with Alyssa Prewett who has the same color eyes and same style of hair as her. The only difference is the side their bangs are on and that Alyssa has red hair and Piper has white (thanks to the twins) which really throws her off the planning track.
Eventually, Harry and Dumbledore leave Hogwarts together to fetch and destroy Merope's locket, thus making Voldemort one step closer to mortal. They must overcome a variety of traps and challenges before reaching the basin where the locket is hidden under a poisonous potion and Harry fights off Voldemort's Inferi. They take the locket and return to Hogwarts as quickly as possible. Dumbledore is quite weak, and when they reach Hogsmeade, they can see that the dark mark is visible above the astronomy tower. Harry and Dumbledore race to the tower. When they arrive, Dumbledore uses his magic to freeze Harry who remains hidden under the invisibility cloak.
Draco Malfoy sprints into the room, threatening Dumbledore's life. Weak and with his wand out of reach, which Alyssa Prewett has on her persons, Dumbledore stalls Draco, telling him that he is not a killer and that the Order of the Phoenix could protect him and his mother from Voldemort. An argument ensues, during which Draco and Alyssa both reveal the dark marks they received before the school year started. After a prolonged argument, the teens lower their wands, and Snape (with other death eaters), pushes into the tower. Harry cannot move or speak, but he hears members of the Order fighting Death Eaters below. Snape raises his wand and kills Dumbledore, sending him flying over the edge of the tower. When Dumbledore dies, his spell on Harry is broken, and Harry rushes after Snape, determined to avenge his friend and headmaster. Snape escapes, and Harry is devastated. He looks at the locket he and Dumbledore retrieved and realizes that it is not a Horcrux. Inside the locket is a not from someone named "R.A.B." Harry tells his friends that he will not be returning to Hogwarts next year and will instead search out and kill Voldemort destroying all of the Horcruxes. Ron and Hermione vow to join him. Ron then reveals to Harry that Alyssa Prewett is his cousin and that she now has to live with the Weasley's because her mother is dead.