More than 80 fire trucks were sent to the decades-old landmark after the blaze broke out late Sunday, the Bureau of Fire Protection said.
Thick, black smoke billowed hundreds of metres into the sky as flames gutted the neo-classical Manila Central Post Office that overlooks the Pasig River.
It took firefighters more than seven hours to get the inferno under control.
"The whole building has burned down from the basement all the way to the fifth floor," Postmaster General Luis Carlos told DZBB radio.
The cause of the blaze was being investigated, he said.
Fire brigades from across the capital deployed personnel to fight the blaze that left one volunteer firefighter with minor injuries.
Originally built in 1926, the post office was once considered the "grandest building" in Manila, according to its website.
It was destroyed in World War II as US forces recaptured the capital from Japanese occupation forces, and rebuilt in 1946.
The Philippine National Museum declared the building an "important cultural property" in 2018.
Letters, parcels and the postal agency's entire stamp collection were in the building and are likely destroyed, Carlos said.
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