The veteran Serb, a seven-time winner at the All England Club, won 6-1, 6-7 (7), 6-2, 6-2 against French world number 41 Alexandre Muller.
He dominated the first set on Centre Court, breaking three times, but Muller levelled the match after taking the second set tie-break.
Sixth-seeded Djokovic resumed normal service in the third set, and a couple of breaks in the fourth set sealed the deal.
"I enjoyed myself, obviously a bit less in the second set, but I went from feeling my absolute best for a set and a half to my absolute worst for about 45 minutes," said Dkokovic.
"Whether it was a stomach bug, I don't know what it is. I struggled with that, but the energy came back after some doctors' miracle pills, and I managed to finish the match on a good note."
Djokovic said he was delighted to be back at Wimbledon.
"I have to acknowledge the sacredness of this court, of this tournament," he said. "It has always meant a lot to me and many other players. It's a childhood dream tournament, so I never take anything out on the court for granted."
He has been tied with long-retired Margaret Court on 24 Grand Slam singles titles since 2023 and he believes his most realistic hope of a historic 25th win lies at the All England Club.
Djokovic, who has lost the past two Wimbledon finals to Carlos Alcaraz, has the added incentive of pulling level with the retired Roger Federer, who won a record eight men's titles at the All England Club.
He has been in every Wimbledon final since 2018, but at 38, he knows time is running out as Alcaraz and Jannik Sinner establish a stranglehold at the top of the men's game.
