The operation on Sunday will allow for the safe defusal of the 1,400-tonne British bomb, which German media said was nicknamed "Wohnblockknacker" (blockbuster) during the war for its ability to wipe out whole streets or buildings.
The unexploded bomb was discovered yesterday during building work a stone's throw from the Westend Campus of the Goethe University Frankfurt, police said in a statement.
Officers are guarding the site and there "is currently no danger".
"Due to the large size of the bomb, extensive evacuation measures must be taken," police said.
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The Wismarer street where the ordnance was found is close to the city centre and just some 2.5 kilometres north of the main Zeil shopping area.
More than 70 years after the end of the war, unexploded bombs are regularly found buried on German land, legacies of the intense bombing campaigns by the Allied forces against Nazi Germany.
One of the biggest such evacuations to date took place last Christmas, when another unexploded British bomb forced 54,000 people out of their homes in the southern city of Augsburg.