DeSantis, a possible contender for the Republican presidential nomination in 2024, turned away Democratic Representative Charlie Crist, Edison Research projected.
Seven Republicans also won U.S. Senate seats, according to Edison, though none was unexpected.
Thirty-five Senate seats and all 435 House of Representatives seats are on the ballot.
Republicans are widely favored to pick up the five seats they need to control the House, but control of the Senate could come down to tight races in Pennsylvania, Nevada, Georgia and Arizona.
In Maricopa County, Arizona - a key battleground - the Republican Senate nominee, Blake Masters, and the national party filed an emergency lawsuit seeking to extend voting hours after some tabulation machines malfunctioned.