The top-seeded partnership, which won their first tournament together at Wimbledon in July, pushed their team record to an unblemished 10-0 with the win over the number three seed.
Hingis, a former world number one singles player who won the U.S. Open title 20 years ago, praised her partner, who is the brother of world number two Andy Murray.
"He's a great partner to have. His wingspan as you saw at the end," she said, referring to Murray's reaching overhead smash that ended the tight super-tiebreaker to cap off the contest.
Murray said his younger brother, who withdrew from the tournament with a hip injury, congratulated him after the match.
"He texted me and said well done," he told reporters.
It is Hingis' second U.S. Open mixed doubles crown in three years and seventh mixed title overall.
Murray also won a mixed title at Wimbledon in 2007.
The tournament was the first for the partnership of Chan and Venus, who needed three sets to win all six of their matches leading up to the final.
(Reporting by Rory Carroll, editing by Gene Cherry)
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