Hingis and Pennetta were making headlines throughout the US Open fortnight with a dream run - as an unseeded pair they took out three seeded teams en route to the final, including two of the favorites, No.5 seeds Kveta Peschke and Katarina Srebotnik and No.3 seeds Cara Black and Sania Mirza.
And it looked like they were going to keep that run going as they stormed through the first set of the final, 6-2, but the No.4-seeded Makarova and Vesnina never stopped fighting, continuing to attack and come in as much as they could, eventually rallying past Hingis and Pennetta, 2-6, 6-3, 6-2.
"We played really well tonight," Vesnina said afterwards. "We cannot believe we won the title. I think it was a great final, too, very entertaining. We'd really like to thank everybody who came to support us."
"It definitely feels amazing to win this title," Makarova said. "It's been a great two weeks for us, and it's just an unbelievable feeling to play on such a great stadium with such a great crowd out there."
Makarova and Vesnina's first Grand Slam doubles title came at the French Open last year. They are the second all-Russian duo to win a Grand Slam doubles title together, after Svetlana Kuznetsova and Vera Zvonareva, who won the Australian Open in 2012. Makarova and Vesnina are the first to win two.
Hingis and Pennetta, who teamed up for the first time during the grass court season, may not have come away with their first Grand Slam title together, but their hopes are high for the future.
"We didn't make it today, but we're really happy to make the final here after just four tournaments together," Pennetta said. "It's amazing. We've had such good results, so we'll just keep going."
"We teamed up in the middle of the season and two months later we're here in the finals of the US Open - I could have only dreamed of this when we started playing together," Hingis said. "It's been an incredible journey here. They were just too good today, so I'd like to congratulate them."
What's next for former World No.1s Hingis and Pennetta? "We'll go to Asia - definitely Wuhan and Beijing - and do our best there, and then next year there's again four Grand Slams," Hingis said.