Police were called to Princes Wharf about 10pm on Monday after reports a man and woman had fallen into the water.
The woman was able to swim to a nearby ladder, get out of the water and raise the alarm.
"The man, who could not swim, struggled to stay on the surface," Detective Inspector David Gill said.
"Two passing members of the public initially entered the water to help the man, with police attending shortly afterwards finding all three men struggling."
Members of the public tried to help before police officers pulled the man from the River Derwent. (Ethan James/AAP PHOTOS)
Three police officers pulled the man onto a police vessel moored nearby, with the two members of the public climbing out of the River Derwent using a ladder.
The man could not be revived by police or paramedics.
"We're in the process of notifying next of kin so we're unable to provide further details about the victim at this stage," Det Insp Gill said.
"I would like to recognise the heroic efforts of the passing members of the public who entered the water in an attempt to rescue the man (and the) outstanding efforts of our responding police and emergency service personnel under very difficult circumstances."
There were people in the area at the time, including people fishing, police say.
Princes Wharf is a short walk from the Hobart CBD and features restaurants and bars.
Two Victorian men have drowned in separate incidents at the city's waterfront in recent years.
Dr Robert Bo Xu died in November 2019 and Jarrod Robert Davies, who was visiting Tasmania with his father, died in February 2020.
An inquest into their deaths, which is yet to provide findings, has been told both men consumed a considerable amount of alcohol before falling into the water.
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