As Lord Voldemort and the Death Eaters commit crimes in both the magical and Muggle worlds, Minister of Magic Cornelius Fudge is replaced by Rufus Scrimgeour. In the second chapter, Professor Snape, appearing to have rejoined the Death Eaters and Lord Voldemort, is visited by Narcissa Malfoy and Bellatrix Lestrange. A terrified Narcissa tells Snape that her son Draco has received orders from Lord Voldemort, and asks Snape to make an Unbreakable Vow with her to protect her son and do the job for him, should Draco fail. Snape agrees, and the vow is sealed.
Harry Potter accompanies Albus Dumbledore on a trip to persuade retired Hogwarts professor Horace Slughorn to return to Hogwarts to fill in the vacant spot in the teaching staff. Harry notices that one of Dumbledore's hands is withered and burnt black, and that he is wearing a ring with a distinctively-marked stone. Harry spends the remaining holiday at The Burrow with the Weasleys and Hermione, where they receive their O.W.L. results. To become Aurors, Harry and Ron must take N.E.W.T. level Potions, but their O.W.L.s in the subject are too low to enroll in Snape's Potions class.
At Hogwarts, Snape is unexpectedly announced as the new Defense Against the Dark Arts instructor, with Slughorn becoming the Potions teacher. Harry and Ron’s O.W.L.s are good enough to enroll in Slughorn’s class, which has lower standards, but neither had purchased a textbook, so Slughorn lends them old Potions textbooks. Harry's book has notes and corrections scribbled all over the pages. Harry discovers that these corrections yield better results than the textbook's instructions, and that the book is inscribed as having previously belonged to the "Half-Blood Prince". As the year continues, Ron dates Lavender Brown but eventually realizes his feelings for Hermione and breaks up with her. Harry realizes that he has feelings (that are conflicting with his friendship with Ron) for Ginny, who has stopped pursuing him and is dating Dean Thomas.
During the school year at Hogwarts, Dumbledore privately tutors Harry, using his Pensieve to show Harry collected memories about Voldemort's past. Dumbledore asks Harry to retrieve a key memory from Slughorn that Slughorn has resisted providing, regarding Slughorn's conversation with a sixth-year Tom Riddle. After disappointing Dumbledore once by not getting the memory from Slughorn, Harry uses Felix Felicis potion (which bestows luck on its drinker) that he had been rewarded with for his newfound "skill" (derived almost entirely from written hints from the Half-Blood Prince) in potion making to gain the memory.
The series of memories reveals that to attain immortality, Voldemort splintered his soul (through committing murders) into six fragments attached to objects called Horcruxes, while leaving a seventh piece in his body. As long as any of the Horcruxes exist, Voldemort cannot be killed. Two Horcruxes have been destroyed: Tom Riddle's diary by Harry in the Chamber of Secrets[HP2] and Marvolo Gaunt's ring by Dumbledore (the ring Harry noticed on his hand earlier). The memories indicate that three other Horcruxes are most likely a locket formerly owned by Salazar Slytherin, a cup formerly owned by Helga Hufflepuff, and the snake Nagini; but the last of the six Horcruxes remains unidentified. Dumbledore speculates that it may be a possession of Gryffindor or Ravenclaw, as Tom Riddle would have wanted a possession of each of the founders of Hogwarts, his first and only real home.
After seeing Harry cast an unusual curse, "Sectumsempra" (a dark curse which leaves deep gashes) against Draco Malfoy, Snape attempts to repossess Harry's Potions book, but Harry gives him Ron's copy instead and hides his copy in the Room of Requirement, noting several other items hidden there over the years. He then distinguishes the cabinet that the book is in with an old bust wearing a wig and a strange looking tiara. Harry gets detention from Snape and misses the Quidditch finals, but Gryffindor wins the Cup with Ron and Ginny starring in the match. During the victory celebration, Harry spontaneously kisses Ginny and they begin dating with Ron's approval.
Dumbledore locates another Horcrux and asks Harry to accompany him to destroy it. They travel to a secret cave to retrieve Slytherin's locket. Harry and Dumbledore find the entrance, present a blood offering to a secret door, and row in a small boat across an Inferi-infested lake. To acquire the locket, Dumbledore must drink a mysterious potion. After drinking the potion, Dumbledore faints, and while attempting to minister to him, Harry provokes the inferi which attack him and Dumbledore. Harry retrieves the Horcrux and guides Dumbledore to safety in Hogsmeade, but as they arrive they see the Dark Mark hovering over the Astronomy Tower at Hogwarts and hurriedly return to the school.
Dumbledore and an Invisibility Cloaked Harry are confronted atop the tower by Draco Malfoy, and before Harry can reveal himself, Dumbledore immobilizes Harry. Malfoy disarms Dumbledore, who sacrificed the time to defend himself to immobilize Harry. Draco admits that he was behind a series of attacks on Hogwarts students, and that Voldemort has ordered him to kill Dumbledore. Dumbledore offers Draco the chance to change sides, and promises to hide Draco and his mother where Voldemort will never find them. Draco cannot bring himself to kill the headmaster, even with the urging of fellow Death Eaters once they arrive. Snape arrives and kills Dumbledore. Harry, enraged and freed from immobility by Dumbledore's death, pursues Snape, who reveals that he is the "Half-Blood Prince" and duels Harry until he gets outside Hogwarts grounds and disapparates.
Harry recovers the locket from Dumbledore's body, only to discover it is a fake left by someone with the initials R. A. B. who had apparently stolen the real Horcrux and left a note about his opposition to Voldemort. The school year ends abruptly with Dumbledore's funeral. He is buried along with his wand beside the lake on Hogwarts's grounds. The fate of the school is uncertain, but Harry vows not to return to school and to hunt for the remaining Horcruxes. Harry breaks up with Ginny to keep her safe from danger during his quest, and Ron and Hermione pledge to accompany him.