The Bloody Tower is most strongly associated with the supposed murder of the 12-year-old Edward V and his younger brother, Richard, in 1483. Tradition says that they stayed in these rooms on the orders of their uncle, the future Richard III.

The most famous and haunting deaths associated with the Bloody Tower at the Tower of London are those of the "Princes in the Tower"—12-year-old Edward V and his 9-year-old brother Richard, Duke of York. In 1483, the boys were declared illegitimate and imprisoned in the tower by their uncle, who became King Richard III; they were never seen alive again, and it is widely believed they were murdered there, though the mystery remains unsolved. Another notable figure associated with the Bloody Tower is Sir Walter Raleigh, who spent 13 years imprisoned there. While Raleigh did not die in the tower—he was eventually executed at Westminster in 1618—he famously attempted suicide there by stabbing himself in the chest. Other high-profile prisoners, such as the Duke of Northumberland (executed 1553) and Judge Jeffreys (who died of kidney disease while imprisoned there in 1689), contributed to the tower's grim reputation. The name was changed from the "Garden Tower" to the "Bloody Tower" in the late 16th century specifically because of the pervasive belief that the young princes had been smothered within its walls.