Second seed Zverev fell 1-6, 7-6 (12/10), 6-0, with the German collapsing to defeat in front of a passionate crowd that roared on 18th-seeded Italian Darderi.
But as expected, top seed Sinner outclassed qualifier Pellegrino on centre court in a match which was in truth never much of a contest.
The 24-year-old Sinner has now won 31 straight matches in Masters 1000 events to equal Novak Djokovic’s record run.
“I’m very happy about the outcome, but at the same time I’m very happy for him, I know he’s working very hard,” said Sinner of Pellegrino.
“Tomorrow, a day off is important for me, trying to rest, and then hopefully I’m ready for quarters.”
Pellegrino’s arrival in the last 16 of his home tournament is by far his best result in a Masters 1000 event.
The 29-year-old is set to move up to a career-best world ranking of 123rd after not just making the main draw of a top-ranked ATP tournament for the first time but also getting to face his country’s biggest sporting star in front of over 10,000 fans.
Pellegrino received warm cheers as he put in a creditable performance against the dominant force in tennis, and he also showed some deft technique when given room to breathe by Sinner.
But Sinner was never in top gear and still comfortably dealt with Pellegrino to set up a clash with 12th seed Andrey Rublev.
Should Sinner win a record-extending sixth straight Masters 1000 title, he will be the first Italian to win at the Foro Italico since Adriano Panatta 50 years ago.
With great rival Carlos Alcaraz out injured and Zverev now gone, Sinner is red-hot favourite for victory as he builds towards completing the career Grand Slam at Roland Garros.
Zverev, the 2024 champion in Rome, slumped in three sets as Darderi rallied to his first ever win over an opponent ranked among the world’s top 10 players.
“It’s my most important win, to beat Zverev at Roma is the most exciting win of my career,” said Darderi. (AFP)