Japan's Naomi Osaka beat Victoria Azarenka 1-6, 6-3, 6-3 in the final to add to winning the 2018 US Open and the 2019 Australian Open.
Japan's Kei Nishikori, the 2014 US Open runner-up, said Sunday he has contracted COVID-19 and has withdrawn from an ATP event in New York with this year's US Open only two weeks away.
Kei Nishikori, who has slipped to 13, said he was disappointed not to be able to begin his season as hoped for in January.
Karolina Pliskova struggled into the second round of the US Open on Monday while 2014 runner-up Kei Nishikori of Japan needed only 47 minutes to advance.
Rafael Nadal is chasing a 12th French Open title while 2009 champion Roger Federer is playing in the tournament for the first time since 2015.
Eighth seed Kei Nishikori began to suffer early in the first set and was a shadow of his usual fighting self as he lost it in 31 minutes.
Novak Djokovic came through an almost three-and-a-half hour, four-set grind that extended into the early hours of Tuesday.
Novak Djokovic remained on course for a record seventh Australian Open title but will next have to conquer marathon man Kei Nishikori.
US Open champion and fourth seed Osaka swept past Slovenia's Tamara Zidansek 6-2, 6-4.
The Japanese had set his sights on returning to the world's top five after falling to 39 last April due to a wrist injury.
Daniil Medvedev beat Andy Murray in straight sets in the Brisbane International on Wednesday.
The 31-year-old Scot had intended to play in Brisbane at the beginning of 2018 but was forced to withdraw with a hip injury.
Roger Federer is now in danger of failing to qualify for the semi-finals for just the second time in 16 appearances at ATP Finals.
Roger Federer and Novak Djokovic, along with six fellow tennis stars travelled to Westminster by the London Underground.
Third seed Nishikori won the last of his 11 career titles in Memphis two years ago.
Novak Djokovic boasts a 14-4 lead over Juan Martin del Potro in a 10-year rivalry, including two wins without dropping a set at the US Open in 2007 and 2012.
Third seed Juan Martin del Potro, the champion in 2009, was 7-6 (7/3), 6-2 ahead when Rafael Nadal retired.
Two-time champion Novak Djokovic ended John Millman's fairytale US Open run on Wednesday, beating the 55th-ranked Australian in straight sets to book a semi-final clash with Kei Nishikori.