The first US presidential debate between Donald Trump and Democratic challenger Joe Biden will take place in Cleveland on 29 September.
It had been due to take place at the University of Notre Dame in Indiana but was changed due to concerns over the coronavirus pandemic.
It will now be co-hosted by Case Western Reserve University and the Cleveland Clinic.
The two men will hold three debates in all before the 3 November vote.
Reverend John I Jenkins, president of Notre Dame in South Bend, Indiana, said the health precautions needed to stage the event "would have greatly diminished the educational value of hosting the debate on our campus".
The new location will be at Western Reserve University's Health Education Campus, the Commission on Presidential Debates said.
The second presidential debate on 15 October will take place in Miami after getting shifted from the University of Michigan.
The third will take place in Nashville on 22 October, while a debate between Vice-President Mike Pence and the Democratic vice-presidential nominee - who has still to be chosen - will be held on 7 October in Salt Lake City.
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Mr Biden is currently holding a lead of 15 percentage points nationally, a Washington Post-ABC News poll suggests.
The president's national approval ratings have dropped in a year dominated by coronavirus - of which the US has by far the world's highest death toll with more than 147,000 - and widespread protests over the death of black man George Floyd in police custody in May.