The Indo-Russian pair fell short against the class of their American opponents, losing 3-6, 7-5, 6-4 amid closed roof of the Centre Court at SW19. The fourth seeds, who had stunned top seeds Bob Bryan and Liezel Huber in semi-final on Saturday, lost a close match lasting a little over two hours.
It was a second Grand Slam final appearance of the year for Paes and Vesnina after they finished runners-up at the Australian Open.
Paes was aiming for his fourth mixed doubles title. He overall has six mixed doubles and seven doubles Grand Slam trophies to his name. Vesnina is yet to win a major after finishing runners up six times in the two doubles events.