World number 18 Keys, who had not reached a WTA final since her defeat to Sloane Stephens at the US Open in 2017, took 1hr 46 min to complete a 7-6 (7/5), 6-3 win over Danish fifth seed Wozniacki.
It marked the fourth title of Keys career and her first since winning at Stanford in 2017.
Her win also completed a superb week in South Carolina, where she defeated three Grand Slam champions — Jelena Ostapenko, Stephens and Wozniacki — to take the title.
After winning a close opening set on a tiebreak, Keys took control of the second set with a stroke of good fortune.
A netcord earned her a break to go 4-2 up, and from there she was not going to surrender the initiative and duly closed out the set to complete the win.