Djokovic has not competed in the United States since the 2021 U.S. Open final and was subsequently denied entry into the country because he is not vaccinated against COVID-19.
He was far from his best in his 46 minutes of action, facing break points at 1-1 before serving his way out of trouble.
Davidovich Fokina took a medical timeout away from the court to tend to a lower back issue while trailing 3-4 and when he returned his movement was limited and he was broken at love.
Handed the opportunity to serve out the set against the ailing Spaniard, Djokovic played an uncharacteristically sloppy game, dumping a forehand into the net to hand the break back.
But the 23-time major winner recovered, flicking a forehand crosscourt passing shot in the next game to capture the opener.
In the first game of the second set, Davidovich Fokina took a step that further aggravated his back injury and soon after walked to the net to shake hands with Djokovic.
"It's great for me to be able to come back to the court and to win a match but obviously mixed emotions with the way it finished," said Djokovic.
"Nevertheless I'm hoping I can build my form day to day and progress through the tournament raising my level."
Up next, Djokovic is meeting with the resurgent Gael Monfils, who beat Alex de Minaur in straight sets earlier in the day.
"He's an amazing guy, someone I truly respect and like a lot as a person," said Djokovic, who holds an astounding 18-0 record against the Frenchman.
"He brings so much joy to the fans, so much entertainment. He's one of the most charismatic players we've had in the last two decades on tour and he's playing better than ever."
Djokovic, who has seen fans pack into his practice session and who played in a doubles match on Tuesday, could be on a collision course at the U.S. Open tune-up with world number one Carlos Alcaraz, who bested him in the Wimbledon final last month.
LAJOVIC UPSETS SINNER
Earlier, Serbian Dusan Lajovic upset world number six Jannik Sinner 6-4, 7-6(4) to reach the third round.
The 66th-ranked Lajovic struck 20 winners in a confident performance to claim his fourth win over a top-10 player this year and next faces American Taylor Fritz, who comfortably beat Italy's Lorenzo Sonego 6-4, 7-6(1).
Sinner earned his first Masters 1,000 title days ago in Toronto but was unable to keep the momentum alive, failing to convert any of the five break point chances he had across the match.
"I obviously knew that it was going to be tough because whenever you are playing somebody who is in great form and has a lot of confidence, they play well in the important moments," Lajovic said.
Former champion and third seed Daniil Medvedev cruised past Italy's Lorenzo Musetti 6-3, 6-2, breaking the Italian twice in each set and winning 82% of his first-serve points en route to victory in 77 minutes.
Australian Open finalist Stefanos Tsitsipas dropped only three first-serve points to beat American Blake Shelton 7-6(3), 7-6(2) and set up a meeting with Poland's Hubert Hurkacz, who ended Borna Coric's title defence.
"We didn't play a lot of rallies today, which was difficult to get into the rhythm," said Tsitsipas. "He was serving big today, he wasn't giving me a lot to work with and I had to hang in there, wait for my chances."
In the final match of the day, veteran Swiss Stan Wawrinka turned back the clock to overpower American 16th seed Frances Tiafoe 6-3, 6-4.
Wawrinka put on a vintage performance and crushed his 11th ace on match point for his 27th win of the year.
Next up for the three-time Grand Slam champion is a first time meeting with Max Purcell after the Australian upset third seed Casper Ruud in three tight sets to reach the round of 16.
