The unseeded 29-year-old brings the curtain down on a career that saw her win 30 WTA titles, with her sole Grand Slam triumph coming in 2018 at Melbourne Park.
Naomi Osaka is the first woman to win two major championships in a row since Williams picked up four straight in 2014-15 and has clearly marked herself as tennis' new star.
Gutsy Andy Murray fought to the end before losing an epic farewell match at the hands of Roberto Bautista Agut. But it was business as usual for ruthless Roger Federer and Rafael Nadal, who joined Caroline Wozniacki in round two.
Caroline Wozniacki who was diagnosed with rheumatoid arthritis, an autoimmune disease which attacks the joints, before the US Open says she is proud of how she has been so positive through it all.
Defending champion Roger Federer defeats Lukas Lacko while sisters Serena Williams and Venus Williams advance to the next round. Meanwhile, world number two Caroline Wozniacki suffers shock defeat against Ekaterina Makarova.
Roger Federer and Serena Williams return to the tournament but hip injury forces Swiss star Andy Murray to withdraw from the championship.
Serena Williams could miss out on being named as one of the 32 seeds for Wimbledon Championships after she took maternity leave for the birth of her first child.
Nadal and Djokovic have played each other 50 times, but their last meeting came more than a year ago, when Nadal won in the Madrid Open semifinals. Djokovic leads Nadal 26-24 overall, but Nadal holds a 13-7 advantage on clay.
Despite the loss in the 29th career meeting between the two sisters, Serena, who is still shaking off the rust after a long layoff, leads their career series 17-12.
More than seven years after appearing in her first Grand Slam final at the 2009 US Open, Wozniacki can finally erase the "but never won a major" footnote that has long been attached to her resume.
Denmark's Caroline Wozniacki faces Romania's Simona Halep in the women's final on Saturday. Wozniacki defeated Belgian Elise Merten 6-3 7-6(2) before Halep won a thriller against Germany's Angelique Kerber 6-3 4-6 9-7 to set up the showdown.
Second-seeded Wozniacki and 2008 runner-up Jo-Wilfried Tsonga had to come back from big deficits. Wozniacki was 5-1 down and facing two match points in third set while Tsonga rallied from 5-2 down in the fifth set.
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