The fourth seeded Indo-Russian pair suffered a 3-6 7-5 4-6 defeat at the hands of second seed Americans after battling for two hours and four minutes.
It is for the second time in this season that Paes and Vesnina have ended runners-up at a tennis Major as they had lost the final of the Australian Open in January to Bethanie Mattek-Sands and Horia Tecau.
Nevertheless, it was creditable performance by Paes after a stormy build up to the Wimbledon, caused by selection drama for London Olympics.
Paes was forced to pair with lower-ranked Vishnu Vardhan after both Mahesh Bhupathi and Rohan Bopanna refused to play with him. Paes was teamed with Sania Mirza for the mixed doubles event.
Although Sania did not refuse to play alongside Paes, she made it clear that her preferred partner was Bhupathi, with whom she has won two Grand Slam titles.
Paes is the highest Grand Slam title winner for India with 13 trophies, six of them are mixed doubles.
In Sunday's match, Vesnina served brilliantly and Paes too played well but the margin of error was little against the strong pair of Mike Bryan and Lisa Raymond, who had a superb all round game.
It was the pair of Paes and Vesnina that got the first chance to go ahead but they squandered a break opportunity in the fifth game of the opening set.
The break chance came about following a brilliant rally by an agile Vesnina at the net.
As if that waste of chance was not enough, Paes dropped his serve in the next game. The Indian saved the first break chance with an ace but could not stop Mike Bryan from converting the second.