Eighth seed Sinner beat the world No. 92 in four sets 6-4, 3-6, 6-2, 6-2 in just over two hours of play.
Djokovic’s seemingly unstoppable progress to a record-equalling eighth Wimbledon men’s singles title, and record-breaking 24th grand slam, is now just two steps away.
The Serb brushed aside spirited Russian No.7 seed Andrey Rublev 4-6 6-1 6-4 6-3 in 12 minutes under three hours on Centre Court on Tuesday.
Sinner has been working with former Australian player Darren Cahill this northern summer, and will be playing his first grand slam semi-final.
Djokovic, in contrast, will be playing his 46th, equalling Roger Federer’s record.
He has won both previous meetings with Sinner, including in last year’s quarter-finals when the Serb dropped the first two sets before coming through in five.
Yet to meet a top-50 opponent at Wimbledon, Sinner was rarely threatened by debutant Safiullin, even though the world No.92 reeled off five games in a row from 1-3 down in the second set to level.
“It means a lot to me. We put a lot of work in, many hours also off the court, a lot of sacrifices for this moment so it means a lot for me and to share it with you guys,” Sinner said.
He later added that cementing his spot in the world’s top 10 had given him the mental edge in grand slams while gaining strength had helped him endure lengthy matches.
“I can stay on court for many hours without suffering,” the 21-year-old said.
Suffering is likely against Djokovic though.
Rublev said he feels like the Serb is playing better and better.
“Every time when he had a chance, this little chance, he (made) them. All of them,” he said.
After conceding the first set in his quarter final, Djokovic restored his authority with a 28-minute demolition in the second, but had to work hard in a third set lasting a minute shy of an hour.
But when that went Djokovic’s way, Rublev’s resistance was broken.
The 36-year-old champion has now won 36 consecutive matches at Wimbledon.
Asked how it felt to be the man always with a target on his back, Djokovic said: “I love it. Any tennis player wants to be in the position where everyone wants to win against you.
“Pressure is a privilege, as Billie Jean (King) said. It’s never going to go away. It awakens the most beautiful emotions in me and it motivates me beyond what I’ve ever dreamed of and inspires me to play my best tennis.
“I know they want to get a scalp, they want to win – but it ain’t happening!”