Djokovic saved two early break points before easing into the matchNovak Djokovic eased to victory at the Cincinnati Open in his first singles match in the United States in two years.
The 23-times Grand Slam champion had been unable to compete in the US over Covid protocols.
But rules for unvaccinated foreign travellers were relaxed in May, enabling him to return to competition.
He won the first set 6-4 against Spain's Alejandro Davidovich Fokina, who later retired with a back issue.
The victory was the 36-year-old's Serb's first time playing singles in Cincinnati since 2019, although he lost in doubles on Tuesday when he and compatriot Nikola Cacic were beaten by Britain's Jamie Murray and Michael Venus of New Zealand.
"Time flies. Four years seems like it was yesterday. It's definitely nice to be back," said the world number two, who will next face Gael Monfils.
"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."
Elsewhere, Australian qualifier Max Purcell beat third seed Casper Ruud in three sets for his first victory over a top-10 ranked player.
Purcell, the world number 70, saved six out of seven break points to win 6-4 3-6 6-4 and set up a meeting with three-time Grand Slam winner Stan Wawrinka.
The swiss former world number three continued his return to form with a 6-3 6-4 win over American 16th seed Frances Tiafoe.
Sixth seed Jannik Sinneralso bowed out, losing 6-4 7-6 (7-1) to Serbian Dusan Lajovic.
Russian third seed Daniil Medvedev moved into the last 16 with a 6-3 6-2 win over Italy's Lorenzo Musetti.
Medvedev, who claimed the title in 2019 before going on to reach the US Open final, faces Germany's Alexander Zverev next.
Zverev won 7-5 6-4 against Japan's Yoshihito Nishioka, while Greek fourth seed Stefanos Tsitsipas and American ninth seed Taylor Fritz both also progressed.
Tsitsipas plays Poland's Hubert Hurkacz, who knocked out Croatian defending champion Borna Coric.
