Since the start of last year, Alcaraz is the only player to beat Sinner more than once and now he's done it four straight times thanks to his emphatic 7-6 (7-5) 6-1 win at Rome's Foro Italico on Sunday.
Alcaraz's victory before Sinner's home fans snapped the Italian's 26-match winning streak, which stretched back to October — when Alcaraz beat him in the China Open final in a third-set tiebreaker.
Alcaraz now leads the career series 7-4 after ensuring Sinner's first tournament back after a three-month doping ban ended in anti-climax.
The Spaniard also solidified his status as the favourite to defend his title at the French Open, which starts next Sunday.
"I'm proud of myself, with the way I approached the match mentally. Tactically, I think I played pretty well from the first point until the last one," Alcaraz said in an on-court interview.
"I'm just really happy to get my first Rome title, hopefully it's not going to be the last one."
Sinner was playing his first tournament since he won his third grand slam title at the Australian Open in January.
In February, he'd agreed to a settlement with the World Anti-Doping Agency that raised questions, since the three-month suspension allowed him not to miss any grand slams, and come back at his home tournament.
He was attempting to become the first home man to win the Italian Open since Adriano Panatta in 1976 and trying to complete a sweep of the Rome singles titles for Italy after Jasmine Paolini won the women's trophy on Saturday.
But despite huge home support, Sinner wasted two set points on Alcaraz's serve when he led 6-5 in the first set and then Alcaraz jumped ahead in the tiebreaker with two aces and held on to seal it.
In the second set, though, Alcaraz moved up a gear to earn a victory that will move the four-time grand slam champion back up to No.2 in the rankings on Monday after his third final in three clay-court events this season.
He won the Monte Carlo Masters and finished runner-up in the Barcelona Open before withdrawing from the Madrid Open because of injury.
Sinner was just glad to be back in business as he thanked his family for their support.
"After three months coming here making this result means a lot to me, a lot to my team also. We worked a lot to be here. Happy also with my family and everything," he said.
"A special thank you to my brother, who, rather than being here, is in Imola to watch Formula 1," he concluded to the laughter of the crowd.
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