The victory made Murray, who won here last year with Martina Hingis, the first man to win consecutive U.S. Open mixed doubles titles since Bob Bryan in 2003-04.
It also marked a triumphant moment for Mattek-Sands, who suffered a horrific knee injury at Wimbledon in 2017.
"It was a little emotional getting that win," said Mattek-Sands. "I thought I did a really good job throughout all the matches, kind of putting that aside and just going out there and playing tennis."
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(Reporting by Frank Pingue;Editing by Peter Rutherford)
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