Bryan, of the United States, and Azarenka, of Belarus, beat top-seeded Katarina Srebotnik of Slovenia and Nenad Zimonjic of Serbia 6-2, 7-6 (4) in the final at Roland Garros.
"We weren't even signed up,'' Bryan said. "I was at the practice court. I rushed over (to the referee's office). Made it with two minutes to go.''
The 10th-seeded pairing of Anabel Medina Garrigues and Virginia Ruano Pascual of Spain won the women's doubles final by beating Casey Dellacqua of Australia and Francesca Schiavone of Italy 2-6, 7-5, 6-4.
It's Ruano Pascual's ninth Grand Slam title, but first with Media Garrigues. The other eight - including four at the French Open - came with the now-retired Paola Suarez.
This was the first doubles tournament together for Dellacqua and Schiavone.
Bryan and Azarenka were seeded third, even though this was their first Grand Slam tournament as a pair. He has won three U.S. Open mixed doubles titles with other partners, in addition to five men's doubles Grand Slam titles with his twin brother Mike.
Azarenka won the 2007 U.S. Open mixed doubles championship with Max Mirnyi.
"Victoria's pretty clutch,'' Bryan said. "I have to give this girl some credit. I knew she was good, but I didn't know she was this good.''
Azarenka reached the fourth round in the women's singles.
Zimonjic and Daniel Nestor of Canada will play Pablo Cuevas of Uruguay and Luis Horna of Peru in the men's doubles final on Saturday.
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