The tournament confirmed 2018 champion Osaka's absence, with the Indian Wells Masters scheduled to take place from 4-17 October after the 2020 edition was cancelled due to the coronavirus pandemic.
Osaka's US Open title defence came crashing down in a remarkable 5-7 7-6 (7-2) 6-4 third-round capitulation at the hands of eventual finalist Leylah Fernandez earlier this month.
Up a set and serving for the match at 6-5 on Arthur Ashe Stadium, four-time major champion Osaka lost her cool and composure after throwing her racquet three times in an unsuccessful second-set tie-break.
Amid boos in New York, Japanese star Osaka was also warned after hitting a ball into the crowd at Flushing Meadows.
After the surprise exit, Osaka told reporters she planned to "take a break from playing for a while."
"I feel like for me recently, like, when I win I don't feel happy," Osaka said. "I feel more like a relief. And then when I lose, I feel very sad. I don't think that's normal. I didn't really want to cry.
"I feel like… this is very hard to articulate. I feel like I'm kind of at this point where I'm trying to figure out what I want to do, and I honestly don't know when I'm going to play my next tennis match [tearing up]. Sorry."
It comes after a difficult couple of months due to mental health concerns as a result of "long bouts of depression" since winning the 2018 US Open.
Osaka withdrew from May's French Open having won her first-round match, after she was fined and threatened with further punishment – and possible expulsion from the grand slam – for skipping obligatory media duties.
She subsequently pulled out of Wimbledon before returning for the Olympic Games, though she suffered a surprise loss on home soil in Tokyo and was reduced to tears during a news conference in Cincinnati.