Italian Sinner bested 17th seed Cerundolo 7-6(2), 6-3 in a match which was delayed by a couple of hours due to a torrential downpour to set up a last-eight clash with either Casper Ruud or Jaume Munar.
Cerundolo knocked out Sinner in the last 16 the last time he played here in 2023, but that was before the 23-year-old had became the tournament-winning machine he is today.
Sinner is finding his feet in Rome, his first tournament since the end of a three-month suspension accepted in February from the World Anti-Doping Agency (WADA) following two positive tests for traces of clostebol in March last year.
His true target is the French Open which follows his home event and he showed some signs of rediscovering the form which has won him three Grand Slams and last year's ATP Finals.
"I'm very happy because today I felt that I raised my level. Game-wise I felt a little bit better," he said.
"I'm happy to be back. I was three months out so, you know, every situation for me I feel very fortunate to be here."
Sinner had to battle through the first set against spirited Cerundolo but once he prevailed in the tie-break he built up an unassailable lead by winning four games in a row in the second.
The packed centre court stands hailed their hero after he took the win at the fourth time of asking and continue his bid for a first Rome title.
Musetti defies Medvedev
The rain which delayed Sinner's match had a much bigger impact on his compatriot Lorenzo Musetti, who reached the last eight after having to wait nearly three hours at match point before he could finish off his victory over Daniil Medvedev.
World number nine Musetti will face either reigning Rome champion Alexander Zverev in the last eight after seeing off Medvedev 7-5, 6-4.
Musetti held his nerve to win on the first point after the long break and made sure that his first week in the top 10 of the world rankings would bring another solid run in a big tournament, after he reached the final in Monte Carlo and the last four in Madrid.
Organisers later said that Musetti would have to pull out of his doubles campaign alongside Lorenzo Sonego due to an injury to his right arm.
Fellow Italian Jasmine Paolini was playing on centre court at the same time as the first part of Musetti's match but managed to complete her comeback from a set down to beat Diana Shnaider 6-7(1), 6-4, 6-2 just before the worst of the weather hit.
Paolini is the first Italian woman to reach the Rome semi-finals since 2014, when her doubles partner Sara Errani got to the final only to be soundly beaten by Serena Williams.