This year's Flushing Meadows final comes on the 12th anniversary of her second victory at the competition when she beat her sister Venus Williams 6-4 6-3 in the 2002 final.
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Serena had announced her arrival on the WTA tour three years earlier with a win in the 1999 US Open at just 17 years of age, two years after Venus reached the final at the same event.
The older of the Williams sisters had initially been the more successful, winning four Grand Slams over the course of 2000 and 2001, but Serena had been outperforming her big sister in 2002, beating her in the French Open and Wimbledon finals to replace her as the WTA's top ranked player.
Despite facing the likes of Lindsay Davenport and Daniela Hantuchova on the way to the final, Serena set up the showdown with her sister, who had beat her in the final in 2001, without dropping a set.
The defending champion made a series of errors in the match, serving 10 double faults to allow her younger sister to pick up an early break.
The sisters appeared to have put their family ties to one side as they chased down every point, both hitting their shots with ferocious power, while Serena complained to the umpire when a wide shot from Venus was missed by the line judge.
While Venus fought hard to match her in-form opponent, Serena had a break again in the second, and brought up two match points while her sister was serving at 5-3.
The 2001 champion saved them both, but another double fault gave Serena a third chance, and this time she wrapped up the title, getting the better of her sister with a powerful backhand return.
The win marked the fourth straight year that one of the Williams sisters had lifted the trophy at Flushing Meadows, and gave Serena the fourth Grand Slam of her career.
Having already won the French and Wimbledon that year, the 2002 US Open was the third leg of what became known as the 'Serena Slam', as Williams went on the secure her first Australian Open title the following January to hold all four major titles at once.
Venus avenged the defeat at the 2008 Wimbledon championships, beating her sister, who was the defending champion, to secure her fifth title at SW19, although Serena has a 7-4 winning record from their 11 Grand Slam meetings to date.
Serena has gone on to be the dominant force in women's tennis for over a decade, with five titles from the Australian Open, Wimbledon and US Open to her name, as well as two victories at Roland Garros, plus wins at the tour finals, the 2012 Olympics and 13 doubles Grand Slams alongside Venus.