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The second-ranked Japanese star will next face the winner of a later match between US 29th seed Jessica Pegula and Greek 23rd seed Maria Sakkari at the WTA and ATP Masters Series event.
“I started off really well and then for some reason I became a little sluggish. My speed didn’t really feel the same,” Osaka said.
“I thought it was really mental from then on. In the end, it was who fought the hardest.”
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Osaka, seeking her first Miami crown, saved a break point with her third ace and finally finished off the first set on her seventh chance with a service winner.
In the second set, Osaka needed her fifth chance of the third game to break Mertens, only for the Belgian to quickly break back to 2-2 and hold to 3-2 before requiring treatment for a right shoulder injury.
Osaka won the last four games after that, breaking at love in the seventh game, holding at love in the eighth and breaking again to end matters after 88 minutes when Mertens netted a forehand.
Top-ranked defending champion Ashleigh Barty battled into the quarter-finals by outlasting former world number one Victoria Azarenka 6-1, 1-6, 6-2.
Australia’s Barty broke five times, the last when Azarenka netted a forehand volley to end matters after one hour and 52 minutes at Hard Rock Stadium.
Barty, who had to save a match point on the way to a three-set victory over Kristina Kucova in the second round, will next face seventh seed Aryna Sabalenka of Belarus, who downed Czech 19th seed Marketa Vondrousova 6-1, 6-2.
“I’m just excited I get to be in another quarter-final of a big event,” Barty said.
“I still feel like there’s a lot better tennis left out there for me. I still don’t feel like I’m playing my very best just yet, but I’m fighting through and I’m finding ways to win, which is great.”
The 2019 French Open winner dominated the first set but Azarenka broke her for a 2-0 lead in the second, then fought back from 0-40 down to hold for 3-0 on the way to forcing a third set, the Aussie failing to a point off her second serve in set two.
Barty and Azarenka traded breaks in the second and third games of the final set. Azarenka denied Barty on two break chances in the fourth game but the 24-year-old Queenslander broke in the sixth to seize the lead and again on the final point.
“First two sets probably had some pretty big momentum swings, but I think the third set was a real tussle,” Barty said.
“It was just about staying the course and over time trying to execute my game plan as best I can and try and kind of bring it back onto my racquet where I felt I was in control a little bit more in that third set.”
Ukraine’s fifth-seeded Elina Svitolina rallied to defeat Czech ninth seed Petra Kvitova 2-6, 7-5, 7-5.
“I’m really happy with how I bounced back from being a set down,” Svitolina said. “I’m happy with how I’m playing and handling the pressure. I had to bring my best game to win.”
Svitolina’s quarter-final foe will be either Croatia’s 338th-ranked Ana Konjuh or Latvia’s 57th-ranked Anastasija Sevastova.
On the men’s side, Russian fourth seed Andrey Rublev routed Hungarian 29th seed Marton Fucsovics 6-2, 6-1, to reach the fourth round.
“I’ve played some great tennis last couple of months,” Rublev said. “We’ll see if I can keep going.”
The 23-year-old from Moscow will next face Croatia’s 32-year-old Marin Cilic, the world number 45 who beat Italy’s 19-year-old Lorenzo Musetti 6-3, 6-4.
“Very pleased,” Cilic said. “Just have to battle it out with these youngsters. I’ve got to keep the heads high for the veterans on the tour.”
Canada’s 19th-ranked Milos Raonic beat 30th-ranked Frenchman Ugo Humbert 6-4, 7-5 and next faces Polish 26th seed Hubert Hurkacz, who dispatched Canadian sixth seed Denis Shapovalov 6-3, 7-6 (8/6).