After winning Wimbledon, the third major of the year, the 34-year-old lost in the bronze medal match to Pablo Carreno Busta at the Tokyo Olympics before pulling out of the mixed doubles citing a shoulder issue.
The 20-time major singles champion has now opted out of the tournament in Cincinnati to focus on preparing for the US Open.
Djokovic said on Twitter: "Dear fans, I wanted to share with you that I am taking a bit longer to recover and recuperate after quite a taxing journey from Australia to Tokyo.
"Sadly, that means I won't be ready to compete in Cincinnati this year so I'll turn my focus and attention to US Open and spend some more time with family. See you in New York soon!"
Djokovic is on the cusp of becoming only the third man in the modern era to hold all four majors in the same year. He defeated Daniil Medvedev to win the Australian Open in January, overcame Stefanos Tsitsipas in June to win the French Open and then defeated Matteo Berrettini to claim Wimbledon last month.
The Serbian was disqualified in last year’s US Open after striking a line umpire with a ball in his match against Carreno Busta and, while the clear favourite to win the title at Flushing Meadows, will need to deal with the pressure and expectation of what he could achieve.
The US Open begins on August 30 and concludes on September 12.
The Masters 1000 series event in Cincinnati is preceded by the National Bank Open in Toronto and there were two first-round exits for Britain’s leading players in the first round.
Dan Evans, currently the British No.1, suffered a straight-sets defeat to Kazakhstan's Alexander Bublik, while Cameron Norrie lost out to Russia’s Karen Khachanov.
Evans made a good start against the mercurial Bublik, breaking his opponent early in the first set, only to be immediately broken back.
And after losing that set, he then immediately found himself a break down in the second en route to a 6-4 6-4 loss in an hour and 40 minutes.
It was a second match for Evans, 31, since losing in the third round at Wimbledon last month and then withdrawing from the Tokyo Olympics after testing positive for coronavirus – last week he lost 7-6 (1) 6-0 to Brandon Nakashima at the Citi Open in Washington.
Bublik will now take on top seed Daniil Medvedev in round two.
Norrie fared better than Evans in that he took a set from Khachanov, who won the silver medal at the Olympics, but he eventually fell to the Russian 6-4 7-5 6-4.
Harriet Dart kept the British flag flying at the Canadian Open in Montreal, however, with a victory over home favourite Leyla Fernandez.
Dart had to come through qualifying to book her place in the main draw and kicked on from there, the 25-year-old overcoming the Canadian in just over two hours with a 7-5 7-6 (4) victory.
The world No.172 draw faces another Canadian in second seed Bianca Andreescu in the next round.