Sinner was pushed to the brink of becoming only the third male defending champion to lose in the Wimbledon first round before battling back to win 4-6, 6-3, 6-7 (6/8), 6-2, 6-3 on Monday.
Trailing by two sets to one, the Italian world number one dug deep to win his first five-set match in his last six attempts.
Sinner’s gutsy victory in three hours and 28 minutes was all the more commendable after he injured his right foot in an awkward fall that left his shoe covered in blood.
He let out a shriek of pain and was motionless for several moments before gingerly resuming play.
With two-time Wimbledon champion Carlos Alcaraz still sidelined by a wrist injury sustained in Barcelona in April, Sinner is the clear favourite to become the 10th man in the Open era to retain the trophy.
He is bidding for his fifth Grand Slam title and his first since his maiden victory at the All England Club last year.
But the 24-year-old hasn’t reached a Grand Slam final this year and crashed out of the French Open in the second round, blowing a two-set lead against Juan Manuel Cerundolo as he wilted in the stifling Paris heat.
Ahead of Wednesday’s second-round clash with Portugal’s Nuno Borges, the Italian insisted he would not be affected by his latest fitness concern.
“I’m good. It just seems much worse than it is. I’m actually very surprised that they let me keep playing because my all white outfit turned into a little red! It is just a nail,” he said.
In Alcaraz’s absence, Djokovic, a seven-time Wimbledon champion, is expected to be one of Sinner’s main rivals.
The 39-year-old Serb is chasing an all-time record of 25 Grand Slam singles titles among men and women.
Djokovic would become the oldest man to win a Grand Slam in the Open era if he lifts the trophy on July 12.
Reaching those historic targets will require a significant improvement from Djokovic, who laboured for over three hours in a 6-4, 5-7, 6-4, 6-4 win over Chinese world number 102 Wu in front of David Beckham and rapper Bad Bunny.
“It was very challenging for me today. I’m feeling happy but not the freshest I guess. It didn’t feel like the first round to be honest,” said Djokovic, who plays Stefanos Tsitsipas in the second round. (AFP)
