Firefighters, police and ambulance crews were called to the property in Hollington Old Lane, St Leonards, at 02:00 BST.
The man was recovered from the house but was later pronounced dead, Sussex Police said.
An investigation is being carried out by East Sussex Fire and Rescue and police but the cause of the blaze is not being treated as suspicious.
A man has died in a fire on the first floor of a house in East Sussex.