The 39-year-old Movistar rider, who grabbed the lead with a brilliant solo performance in the mountains on Saturday, bided her time in the peloton before powering up the final climb to seal her triumph.
Demi Vollering (SD Worx) finished second to claim second overall with Katarzyna Niewiadoma (Canyon/SRAM) third in the final standings after a fourth place finish on Sunday's stage.
Van Vleuten, a three-time winner of the Giro d'Italia and time-trial gold medallist at the Tokyo Olympics, began the 123-kilometre final stage with a 3min 14sec lead over Vollering which was never in danger in spite of having a mechanical problem with her bike 57kms from the finish which required a quick swap with a teammate.
The yellow jersey group reeled in the 11-rider breakaway with five kilometres to go at which point van Vleuten climbed out of her saddle and began powering her way up the final crippling climb.