The fifth-seeded Spanish-Argentine duo reaffirmed their dominance over the sixth seeds, who they beat to claim their first major together at the French Open in June before ousting them again in the Wimbledon quarter-finals a month later.
"It was an amazing battle," 40-year-old Zeballos said. "These matches are so unfair when there is a winner and a loser. The guys (Britons) did great and they also deserved to win.
"I can't believe we just won the US Open. It's so beautiful to be here. It's always tough to find a good crowd for doubles, but you guys are amazing."
Granollers and Zeballos, who lost a US Open final back in 2019, found themselves on the back foot early under the Arthur Ashe roof, dropping the opening set after a pair of double faults gifted the Britons the only break for a definitive lead.
Granollers and Zeballos dug deep in the second set, saving three break points from 40-0 down at 3-3, reeling off five straight points for a crucial hold.
The set went to a tiebreak, where a double fault and a net error from Salisbury and Skupski handed Granollers and Zeballos the initiative to level the match at one set apiece.
The decider was a serving power battle until the British pair earned three match points, only to see them slip away as Granollers and Zeballos produced a gritty hold.
Riding the momentum, they broke Salisbury and Skupski in the next game before serving for the championship, sealing the title on their second chance following a stunning comeback.
Salisbury and Skupski, who have only played together since the start of the year, had hoped to become the first all-British team to lift the U.S. Open men's doubles trophy since 1903.
"Congratulations to Marcel and Horacio, you have been better than us this year," Salisbury, who has three US Open titles alongside American partner Rajeev Ram, said. "As in Paris, I can't think of two better men to compete against."