The Tigers (13-2) finished with their 10th state championship in school history and eighth since 2003.
Henderson, a sophomore tailback, rushed for 214 yards with touchdown runs of 75 yards in the first quarter and 22 yards in the fourth quarter.
Junior quarterback Rip Kirk finished with 202 yards passing with two touchdowns for South Panola, including a 12-yard TD pass to Henderson in the second quarter.
Brandon's Gardner Minshew passed for 223 yards with a touchdown, a 9-yarder to Dylan Knott, and Davein Tillis had an 18-yard TD run for the Bulldogs (12-3). Jim Speights kicked three field goals from 33, 22 and 23 yards out for Brandon.
Tevis Flowers intercepted a Minshew pass with 43 seconds left to seal the win.