The planned 61-storey Museum Plaza development will house two museums, a 280-room hotel, offices, 133 loft apartments, 82 penthouses and a wealth of shops and restaurants.
Costing US$380 million (£218 million), the building will also become the new home of the University of Louisville's Master of Fine Arts program.
Museum Plaza is being backed by Louisville residents Laura Lee Brown, Steve Wilson, Steve Poe and Craig Greenberg, who 'share a common passion for downtown revitalization.'
Wilson said: 'Ever since we saw the Guggenheim Museum in Bilbao, Spain, we've asked why not in Louisville?
'Since that time it has been our dream to actually make that happen. OMA understands our mission and their designs exceeded our wildest expectations.'
Once built, the scheme will complete the public plaza area along the town's revamped waterfront, between the Muhammad Ali Centre at Sixth Street and the Frazier Historical Arms Museum in Ninth Street.