The fifth-seeded Williams breezed past No. 9 seed Safarova 6-0, 6-1, moving her into third place in career WTA Tour wins among active players.
Williams trails now only her sister Venus (43) and Kim Clijsters (41) in that category.
She started strong by saving all four of Safarova's break point chances in the opening set and cruised the rest of the way.
Safarova, who was seeking her first title since 2008, became the first Czech player to reach the Charleston final since Regina Marsikova in 1980.