He was the son of Henry Stafford, 2nd Duke of Buckingham. His father was attainted and executed for rebelling against King Richard III of England when Stafford was five. When Henry VII ascended the throne, the attainder was reversed and the wardship of the young duke was given to the king's mother Margaret Beaufort. As a young man, Stafford was made a Knight of the Garter (1495), and had various ceremonial roles at the royal court. This continued in an even grander way with the accession of Henry VIII: Stafford became lord high constable, and was lord high steward at Henry's coronation in 1509, where he also carried the king's crown.
Yet the real power in Henry VIII's court was not with the great nobles but with low-born men such as Thomas Wolsey. Stafford, with his royal blood and numerous connections by descent or marriage with the rest of the aristocracy, became a leader of the disaffected nobles. The ever-suspicious king personally examined various witnesses, and had Stafford arrested in 1521. The charges, such as that Stafford had listened to prophecies regarding when the king would die, are generally considered to be trumped-up. It was once maintained that Wolsey was behind the matter, but there is no hard evidence for this.
Stafford was tried before a panel of 17 peers, but with the king's mind already decided, convinction was certain, and he was executed on Tower Hill. He was attainted by act of Parliament on July 31, 1523.
Stafford married Alianore Percy, daughter of Henry Percy, 4th Earl of Northumberland. They had four children: