Having seen Italian compatriot Lorenzo Musetti take Novak Djokovic to five sets earlier on Court Philippe-Chatrier, Sinner made a strong start against the King of Clay.
However, whereas Musetti took two sets from the world number one before being outpunched by Djokovic, Sinner was swiftly reeled back in after spurning a chance to win the first set.
The 19-year-old's spirited efforts were undermined by 40 unforced errors, offering Nadal far too many opportunities to press home the gulf in class and experience in a 7-5 6-3 6-0 win.
Nadal held to love in his first service game and then immediately broke Sinner. However, he was uncharacteristically sloppy across his next two service games, sending down three double faults, as Sinner reversed the tide to surge into a 4-2 lead.
Yet the teenager crumbled as he failed to serve out the set, surrendering a break to love with a double fault.
Then tasked with serving to stay in the set, Sinner had no answer for Nadal, who was now in full flow, an exquisite drop shot bringing up three set points. Sinner saved one, but Nadal's defence forced him into a forehand error that handed the Spaniard his 33rd consecutive set at Roland Garros.
A scorching cross-court backhand saw Nadal craft an early break in the second and he seemingly had a stranglehold on the contest after going 4-0 up.
Sinner surprisingly rattled off the next three games to get back on serve, only to instantly cede the advantage back to Nadal, who subsequently wrapped up the second set with a powerful serve down the middle.
And there was no fightback from Sinner in the third as Nadal coasted to a last-eight clash with Diego Schwartzman, who won earlier against Jan-Lennard Struff.