The 23-times Grand Slam champion was not allowed to compete in the US last year and earlier this year over his refusal to take a COVID-19 vaccine, but returned after the US government relaxed its rules for unvaccinated foreign travellers in May.
Playing singles in Cincinnati for the first time since 2019, the Serbian won the first set 6-4 against Alejandro Davidovich Fokina, who later retired with a back issue.
"Time flies. Four years seems like it was yesterday. So it's definitely nice to be back," Djokovic told reporters. "I've had some really nice memories from this tournament.
"Winning it in 2018 obviously is a highlight for me, because it was the only Masters I hadn't won for years. I think I lost four or five finals mostly to Roger (Federer).
"But I played well in the past and was really glad to have a chance to come back to the States. It's been two years. I missed it. Some of the biggest tournaments in our sport are played on American soil. I'm just excited to play some tennis."
World number two Djokovic, who lost the Wimbledon final to Carlos Alcaraz last month, is looking to capture his third Grand Slam title of the season at the August 28-September 10 U.S. Open.
The 2021 New York runner-up last competed on hardcourts in March and said it was too early to rate his form on the surface after a rusty first match back.
"Some positives, some negatives. But at the end of the day, it's expected. First match coming back," said Djokovic, who will meet fellow veteran Gael Monfils next.
"It'll probably take a few sets for me to really get things going in a right way."
