The 31-year-old American became the oldest Open Era women's winner in US Open history, 293 days older than Margaret Court when she set the prior mark in 1973, and the third-oldest Grand Slam women's champion of the Open Era.
Williams won $3.6 million, including a $1 million bonus for her success in US open tuneup events.
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Williams won a rematch of last year's US Open final that gave her and Azarenka a combined total of six of the eight major titles from the past two years.
Williams improved to 13-3 in their rivalry but two-time Australian Open champion Azarenka had won two of the previous three, most recently in last month's Cincinnati final.
"It was never over until match point," said Williams, who was broken twice in the second set when serving for the match.
"Victoria is such a great competitor. She was really able to push me into a third set. I was really stern with myself. I knew that if I wanted to win, I had to play better."
Azarenka admitted Williams was the superior performer in windy conditions at Arthur Ashe Stadium that baffled both players at times and sent Williams' pink dress fluttering above her waist much of the match.
"It's a tough loss but being in the final against the best player, who deserves the win, it's incredible," Azarenka said. "I gave it everything I had. I fought hard."
Williams matched Steffi Graf for second on the Open Era list with five US Open trophies, one shy of Chris Evert's record, and moved one adrift of Martina Navratilova and Evert for second on the Open Era Slam win list.
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