After her success in the early months of the season, Osaka had a relatively quiet middle of the year. She reached the third round at both the French Open and Wimbledon, matching her best performance at each tournament. The closest she came to winning another tournament was on grass at the Nottingham Open, where she lost to top seed Barty in the semifinals. Osaka did not have another breakthrough result until the US Open, where she won her second title of the year. Like at Indian Wells, she only dropped one set in the middle round of the event, this time to No. 20 Aryna Sabalenka. In the three early rounds, she only lost a total of seven games and notably recorded a double bagel victory against Aliaksandra Sasnovich. Osaka was drawn against Madison Keys in the semifinals, and was able to avenge her tough loss from the 2016 US Open to advance to the final. In the final, she defeated Serena Williams for the second time in 2018 to win her first grand slam title. The match was marred by an on-court dispute between Williams and the umpire highlighted by Williams receiving a game penalty and boos from the crowd both during the match and the award ceremony. Osaka later said that the win was "a little bit bittersweet" and "it wasn't necessarily the happiest memory." Nonetheless, she became the first Japanese woman to contest a Grand Slam singles final and the first Japanese Grand Slam singles champion.
Osaka made her Hopman Cup debut in 2018 with Yūichi Sugita. Japan was making their first appearance at the exhibition tournament since 2001. They were grouped with Switzerland, the United States, and Russia, and lost all three of their ties. Osaka's only match win came in singles against Russian Anastasia Pavlyuchenkova. She also had a big highlight in the mixed doubles match against Switzerland when she served an ace past Roger Federer.
Osaka credited improving her mental approach and cutting down on unforced errors for her breakthrough season in 2018. At the Wuhan Open towards the end of the year, she noted, "I think my biggest improvement is mental. My game is more consistent, there are not so many unforced errors. I'm not sure how many I hit today, but sometimes last year I was hitting a lot!" She attributed some of these changes to her coach Sascha Bajin, saying, "Since I was working with [Bajin] — and I tend to be a bit negative on myself — I feel like I've gotten a little bit more optimistic ... I fight myself a lot, so he's sort of been, like, the peacemaker." Bajin also agreed with Osaka on the impact of having a patient, positive approach in each match.
After a lackluster 2017 season, she switched coaches to Sascha Bajin, who had previously served as a hitting partner to top players such as Serena Williams, Victoria Azarenka, and Caroline Wozniacki. With Bajin as her coach, Osaka won her first Premier Mandatory title and two Grand Slam singles titles. She also rose to No. 1 in the world after having never previously been ranked above No. 40. Bajin was named the inaugural WTA Coach of the Year in 2018. Shortly after her 2019 Australian Open title, Osaka surprisingly split with Bajin, saying, she "wouldn't put success over [her] happiness." She hired Jermaine Jenkins to be her new coach the following month. Jenkins had previously worked as a hitting partner for Venus Williams. Osaka temporarily replaced him with her father in September. She won her first two tournaments with him back as her coach. She then hired Wim Fissette for the start of the 2020 season.