Lord Voldemort is tightening his grip on both the wizarding and Muggle worlds, kidnapping Ollivander from Diagon Alley and destroying the Millennium Bridge. The Malfoy family is disgraced when Lucius is apprehended and sent to Azkaban for his involvement with the Death Eaters. Voldemort instead chooses Draco to carry out a secret mission at Hogwarts. Draco’s mother Narcissa and aunt Bellatrix Lestrange seek help from Severus Snape, who claims to have been acting as a mole within the Order of the Phoenix all along. Snape makes an Unbreakable Vow with Narcissa to protect Draco and fulfill the assignment if he fails.
Harry Potter, now 16 years old, accompanies Albus Dumbledore from Surbiton to the village of Budleigh Babberton to visit former Potions professor Horace Slughorn. Slughorn, who has been in hiding, 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. The three visit Fred and George Weasley’s new joke shop at Diagon Alley and see Draco entering Knockturn Alley with a group of Death Eaters including Fenrir Greyback. Harry believes Voldemort has made Draco a Death Eater, but Ron and Hermione are sceptical. On the Hogwarts Express, Harry hides in the Slytherin carriage using his Invisibility Cloak, but is spotted and petrified by Malfoy. Harry is found and saved by Luna Lovegood.
At Hogwarts, Harry and Ron borrow textbooks for Slughorn’s Potions class, and Harry is stuck with a copy that turns out to be filled with helpful notes and spells left by the “Half-Blood Prince”. Harry uses the book to excel in the class and impresses Slughorn, winning a Liquid Luck potion. Ron becomes Keeper of the Gryffindor Quidditch team and forms a romantic relationship with Lavender Brown, upsetting Hermione. Harry consoles Hermione and admits that he now has feelings for Ron’s younger sister, Ginny Weasley.
Harry spends the Christmas holidays with the Weasleys. On Christmas Eve, Harry discusses his suspicions about Draco to the Order of the Phoenix. His suspicions are dismissed, but Arthur Weasley later tells Harry privately that the Malfoys may have been interested in a Vanishing Cabinet. Bellatrix and Greyback attack and burn down the Burrow, drawing Harry into a battle. He saves Ginny before the Order arrive and fight off the Death Eaters. At Hogwarts, Dumbledore reveals to Harry that Slughorn possesses a memory of Voldemort that Dumbledore desperately needs. He asks Harry to confront Slughorn and retrieve the real memory, after being given an altered version that made it appear as though Slughorn did not know anything. Harry is unable to convince Slughorn.
After Ron accidentally ingests a love potion intended for Harry, Harry cures him with Slughorn’s help. The trio celebrate with mead that Slughorn had intended to gift to Dumbledore. The mead poisons Ron, and Harry is forced to save his life after Slughorn hesitates. Ron murmurs Hermione’s name while recovering in the infirmary, causing Lavender to end their relationship. Harry confronts Draco about the mead and a cursed necklace, and the two duel. Harry uses a curse from the Half-Blood Prince’s potion book to severely injure Malfoy, who is rescued and healed by Snape. 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.
Harry decides to use his Liquid Luck potion to convince Slughorn to give up the memory Dumbledore needs. Harry views the memory with Dumbledore and learns that Voldemort wanted information for creating Horcruxes, magical objects that could contain pieces of a wizard’s soul and make them immortal. Dumbledore concludes that Voldemort successfully divided his soul into seven pieces by creating six Horcruxes, two of which have already been destroyed: Tom Riddle’s diary by Harry and Marvolo Gaunt’s ring by him. The two travel to a seaside cave where Harry aids Dumbledore in drinking a potion that hides another Horcrux, Slytherin’s locket.
A weakened Dumbledore defends them from Inferi and apparates back to Hogwarts. Bellatrix, Greyback, and more Death Eaters enter Hogwarts with Draco’s help through the Vanishing Cabinet in the Room of Requirement that Draco managed to connect to the one he had been working on in Knockturn Alley. Dumbledore instructs Harry to hide and not interfere under any circumstance. Draco arrives in the Astronomy Tower and disarms Dumbledore revealing that he has been chosen by Voldemort to kill the headmaster. Snape arrives, and casts the killing curse on Dumbledore when Draco is unable to bring himself to do it, killing the Headmaster. He then overpowers Harry and reveals himself as the Half-Blood Prince before escaping.
Harry returns to Hogwarts, where the students, staff, and a few guests mourn Dumbledore’s death. He 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 returning for their final year at Hogwarts, the three decide to leave and track down the remaining Horcruxes.