Despenser first played an important part in 1258, when he was prominent on the baronial side in the Mad Parliament of Oxford. In 1260 the barons chose him to succeed Hugh Bigod as Justiciar, and in 1263 the king was further compelled to put the Tower of London in his hands.
He was the son of Hugh le Despenser and was summoned to Parliament by Simon de Montfort. Hugh was summoned as Baron le Despenser on 14 December 1264 and was Chief Justiciar of England and a leader of the baronial party, so he might be deemed a baron, though the legality of that assembly is doubtful. He remained allied with Montfort to the end, and was present at the Battle of Lewes. He was killed fighting on de Montfort's side at the Battle of Evesham in August 1265. He was slain by Roger Mortimer, 1st Baron Wigmore; this caused a feud to begin between the Despenser and Mortimer families.