Harry Potter and the Half-Blood Prince features the exploration of Hogwarts and casting spells on objects around the school, similar to its predecessor. The game also includes multiplayer games, classes, different times of day, Quidditch, Wizard Duels and Potion making. The Marauder's Map is included in the game, with progress opening other parts of the school. Harry can also call Nearly Headless Nick to show him around the school. Harry is the main playable character in the game, but Ron and Ginny are also available in two levels.

In Harry Potter and the Half-Blood Prince, Dumbledore prepares Harry for the final battle that he knows is fast approaching as Voldemort is tightening his grip on both the Muggle and wizarding worlds. Together they work to find the key to unlock Voldemort's defences and, to this end, Dumbledore recruits his old friend and colleague, the well-connected and unsuspecting bon vivant Professor Horace Slughorn, whom he believes holds crucial information about Voldemort's power.