The Bryans, seeded second, topped No. 5-seeds Leander Paes and Radek Stepanek 6-3, 6-4 without facing a break point.
The same teams had played in the men's doubles finals of the Australian Open but Paes and Stepanek won that outing. The Bryans also lost in the finals of this year's French Open.
The Bryans previously won U.S. Open titles in 2005, 2008 and 2010.
The 2012 championship gives them a record-tying 12 Grand Slam doubles championships. Australian players John Newcombe and Tony Roche also won 12.