The blaze broke out at a building of five apartments on Beverley Road at about 06:00 GMT, the fire service said.
The 31-year-old victim was rescued from a ground floor property and taken to Hull Royal Infirmary where he later died.
Humberside Police said the fire was not being treated as arson and described the man's death as "non-suspicious but unexplained".
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Two firefighters also suffered minor injuries, Humberside Fire and Rescue said.
Resident Vitalijus Lisauskas, who lives in the top floor flat, said he believed the explosion was a result of a gas leak.
"The fire was in one of the downstairs flats and luckily we exited out of the building as it happened," he said.
"Then it just exploded... knocking off the window and the one above it as well.
"It looked like a fireball, in a split second it went boom."
His neighbour, who would only give his name as John, said: "All I heard was a loud crash.
"I'm quite a heavy sleeper so I went back to sleep and then the next thing you know I've got the fire brigade knocking and banging on my window telling me I need to get out."
The scene is near Hull and East Riding Institute of the Blind (HERIB).
Beverley Road was closed between Alexandra Street and Queens Road for up to three hours while a cordon was in place around the property.
A man has died following a fire and explosion at a flat in Hull.