The four-time Grand Slam champion from Japan had been on a run of hardcourt form, reaching the Washington semi-finals and the last eight at the ongoing WTA 1000 event in Toronto.
As the 11th seed, Osaka would have had a first-round bye, but said she was just not prepared to play.
"I’m really sad to have to withdraw from Cincinnati this year due to fatigue," Osaka said in a statement. "I love playing here and am looking forward to coming back and competing in Cincinnati next year."
It was her second consecutive withdrawal at Cincinnati. She pulled out last year, blaming a change of schedule.
The 28-year-old last competed in Cincinnati in 2024, when she lost in qualifying rounds as she made a comeback after giving birth.
She finished runner-up at the 2020 edition to Victoria Azarenka.