The top-ranked Serb — attempting to win a title on his tournament debut for the 10th time — beat Australian Alexei Popyrin 6-4, 6-2 and next faces local wild card entry Go Soeda.
Djokovic and Filip Krajinovic had been knocked out of the doubles by fourth-seeded Mate Pavic and Bruno Soares on Monday. That was Djokovic's first competitive match since retiring with a left-shoulder injury during his fourth-round clash with Stan Wawrinka at the U.S. Open.
"My shoulder is good, I didn't feel any pain in today's match," Djokovic said.
"I thought from beginning to end that I played very well, very consistent, high level, good intensity, and plenty of chances on his serve. I was able to step it up in the second set and finished the match well.
Djokovic held four of his nine games to love and did not give any break-point opportunities in the match.
Yet Popyrin had his moments, and it took Djokovic until the ninth game to break. Popyrin led 40-15 before being pegged back to deuce, then saved four break points before succumbing on the fifth.
Japanese wild card Taro Daniel caused the biggest upset of the day by beating second-seeded Borna Coric 6-4, 4-6, 7-6 (5) after a grueling 2 hours, 39 minutes in 30-degree C (86 F) heat on the Colosseum show court.
Lying in wait for Daniel is Jordan Thompson, after the Australian got the better of Juan Ignacio Londero 6-3, 3-6, 6-3.
Daniel's victory means four of the five Japanese in the main draw made it through to the second round, as qualifier Yasutaka Uchiyama needed only 54 minutes to dismantle fourth-seeded Benoit Paire 6-2, 6-2. He next meets Radu Albot, who beat Krajinovic 6-3, 7-5.
Soeda and Yoshihito Nishioka complete the home quartet in the last 16.
Reilly Opelka won an all-American duel with seventh-seeded Taylor Fritz, 6-3, 6-4, to set up a second-round match against Frenchman Gilles Simon, who beat Pablo Andujar 6-4, 6-0.
Canada's Denis Shapovalov won the last match of the evening, 6-4, 6-4 against Miomir Kecmanovic. His next opponent is to be determined, with three first-round matches on Wednesday.
More AP tennis: https://apnews.com/apf-Tennis and https://twitter.com/AP—Sports