The German’s fourth career win will see her rise from her current position of 16th in the world rankings after what has been a disappointing season so far.
Kerber looked to have her trademark defensive game back in full effect and she was relentless against Keys in a gruelling three-set battle in Charleston.
Keys, who beat Kerber in the Eastbourne final last year, looked nervous and out-of-sorts as she was broken three times in the first set.
But the 20-year-old from Illinois battled back in the second, breaking to win the set after a series of serves where Kerber pushed her all the way.
Keys, her confidence fully restored, then broke out to a 4-1 lead in the third set, but Kerber won six of the next seven games, breaking to go 6-5 up and then serving out to love to secure the championship.
“I feel great. Madison is a great player and she played very well today so I think both of us are champions,” said Kerber.
There was also a big win for Sania Mirza in the women’s doubles event, as she became the first Indian player to reach the top of the WTA rankings.
Mirza and Martina Hingis won the Charleston title by defeating Casey Dellacqua and Darija Jurak 6-0 6-4.