The fourth-seeded Russians rallied from down a set and break to beat Hingis and Flavia Pennetta 2-6, 6-3, 6-2 on Saturday night.
Playing doubles in her latest comeback from retirement, the 33-year-old Hingis was in her first major final since the 2002 Australian Open. She has won nine Grand Slam doubles titles to go with her five major singles championships.
"It was an incredible journey," Hingis said.
Makarova and Vesnina also won the 2013 French Open.
Makarova was routed by No. 1 Serena Williams 6-1, 6-3 on Friday in her first major singles semifinal. She and Vesnina beat the Williams sisters in the quarters in doubles.
"Definitely, it was so amazing," Makarova said. "I'm just so happy. It was a great two weeks for me."
Hingis and Pennetta thought they had broken to get the final set back on serve at 3-3, but the Russians challenged, and what had been called a winner was in fact out by about a millimeter. Makarova and Vesnina saved a total of three break points to hold, and they won the next two games to clinch the championship.
Hingis returned to competition last year but lost in the first round of the 2013 US Open with Daniela Hantuchova and this summer's Wimbledon with Vera Zvonareva. She and Pennetta had played in three tournaments together leading up to the US Open.