16-year-old Harry accompanies Albus Dumbledore to visit former Potions professor Horace Slughorn, who has gone into hiding. Slughorn agrees to return to teach at Hogwarts. Dumbledore then takes Harry to the Burrow, where Harry reunites with his best friends Ron Weasley and Hermione Granger. Harry believes Voldemort has made Draco a Death Eater, but Ron and Hermione are skeptical. At Hogwarts, Harry and Ron have to borrow the needed textbooks for Slughorn's Potions class because they don't have their own yet. Harry's copy is inscribed on by the "Half-Blood Prince". This owner has annotated the book with additional instructions, spells and recommendations that allow Harry to excel in the class. Ron becomes Keeper of the Gryffindor Quidditch team and forms a romantic relationship with Lavender Brown, leaving Hermione disconsolate. Harry consoles Hermione, revealing that he now has feelings for Ron's younger sister, Ginny Weasley.
Harry spends the Christmas holidays with the Weasleys. On Christmas Eve, Bellatrix Lestrange and Fenrir Greyback set fire to the Burrow. Back at school, Ron is nearly killed by poisoned mead, a drink originally intended for Dumbledore. While recovering, Ron murmurs Hermione's name, causing his break-up with Lavender. Harry confronts Draco and severely injures him with a Sectumsempra curse taken from the textbook of the Half-Blood Prince. Snape enters and quickly heals Draco's wound. Fearing the book may be filled with more Dark Magic, Ginny and Harry hide it in the Room of Requirement and share their first kiss.
Dumbledore shows Harry memories of a young Tom Riddle and reveals that Slughorn retains a memory critical to Voldemort's defeat. Harry succeeds in retrieving the memory, and learns that Voldemort wanted information for creating seven Horcruxes. Two of Voldemort's Horcruxes have already been destroyed: Tom Riddle's diary and Marvolo Gaunt's ring. After discovering the possible location of another Horcrux, Harry and Dumbledore travel to a seaside cave where Harry is forced to make Dumbledore drink a painful potion that hides the Horcrux, a locket. A weakened Dumbledore defends them from Inferi and Apparates back to Hogwarts, where Bellatrix, Greyback and more Death Eaters have entered with Draco's help through a Vanishing Cabinet.
Dumbledore instructs Harry to hide as Draco arrives, revealing that he has been chosen by Voldemort to kill Dumbledore. However, he is unable to bring himself to do it, and Snape casts the Avada Kedavra curse instead, killing Dumbledore. Harry attempts to curse Snape but Snape overpowers him and reveals that he is the Half-Blood Prince. Harry returns to the school to find the staff and students mourning Dumbledore. Harry later reveals to Ron and Hermione that the locket Horcrux was a fake. The locket contains a message from "R.A.B.", stating that he has stolen the real Horcrux with the intent of destroying it. Rather than return for their final year at Hogwarts, Harry, Ron and Hermione vow to seek out and destroy the remaining Horcruxes.