The Santa Maria, along with the La Nina and La Pinta, were part of Columbus's expedition in 1492, which explored islands in the Caribbean in an attempt to find a westward passage to Asia.
The flagship, which was the largest of the three ships, was lost during the expedition, shortly before Columbus returned to Spain.
Mr Clifford told CNN he identified the potential location of the Santa Maria through earlier archaeological findings that pinpointed a likely location for Columbus's fort - a building that experts always thought was erected near to where the ship ran aground.
He also used information from the explorer's diary, and a recent diving mission near the site further burnished Mr Clifford's belief the wreck was the Santa Maria.
The ship was found in the exact area where Columbus said the Santa Maria ran aground more than 500 years ago, Clifford said. The wreck is stuck on a reef off Haiti's northern coast, 10 to 15 feet beneath the water's surface. Mr Clifford said the "smoking gun" was a cannon of 15th Century design found at the site.