World number one Djokovic cruised into the last 16 in Paris for the 12th consecutive year, the longest such streak at Roland Garros in the Open era.
He swept past 93rd-ranked Ricardas Berankis 6-1, 6-4, 6-1 on Saturday, making short work of the Lithuanian for the second French Open in a row.
He will next face a player who became just the sixth man since 2000 to make the fourth round of a major on his debut.
“I really like how he plays. He’s got a lot of firepower from both forehand and backhand,” Djokovic said ahead of a first meeting with Musetti.
“He’s got really all-around game. Not just for clay. Probably, maybe his biggest wins he made on the hard court so far.”
Djokovic reached the French Open final last year for the first time since winning the 2016 tournament.
In contrast, the 19-year-old Musetti is appearing in his first Grand Slam main draw, having twice fallen in qualifying for the Australian Open.
Musetti overcame 2018 Roland Garros semi-finalist Marco Cecchinato in five sets to extend his debut run, taking his fifth match point to seal a 3-6, 6-4, 6-3, 3-6, 6-3 win.
SVITOLINA KNOCKED OUT
Meanwhile, Elina Svitolina became the seventh top-10 seed to be knocked out in the opening week as she fell in the third round to Barbora Krejcikova.
Fifth seed Svitolina’s serve was broken six times as she was outclassed 6-3, 6-2 by the impressive unseeded Czech.
The Ukrainian follows Ashleigh Barty, Naomi Osaka, Karolina Pliskova, Aryna Sabalenka, Belinda Bencic and Bianca Andreescu out of Roland Garros.
However, defending champion Iga Swiatek and fourth seed Sofia Kenin advanced.
American Kenin looked in danger of joining the casualty list when she lost the opening set from 3-0 up by surrendering three successive service games to compatriot Jessica Pagula.
But her aggressive approach ultimately paid off against a more passive Pagula as Kenin hit 48 winners to triumph 4-6, 6-1, 6-4. Swiatek, meanwhile, made a wobbly start against Estonian 30th seed Anett Kontaveit by dropping her opening service game but recovered to take the first set to a tie-break, which she dominated. A 55-minute opening set made way for a swift second where the 20-year-old Pole did not drop a game, taking a 7-6(4), 6-0 victory.
Results:Third round: Men: R Nadal bt C Norrie 6-3, 6-3, 6-3; N Djokovic bt R Berankis 6-1, 6-4, 6-1; J Sinner bt M Ymer 6-1, 7-5, 6-3; J Struff bt C Alcaraz Garfia 6-4, 7-6(3), 6-2; L Musetti bt M Cecchinato 3-6, 6-4, 6-3, 3-6, 6-3; D Schwartzman bt P Kohlschreiber 6-4, 6-2, 6-1; S Tsitsipas bt J Isner 5-7, 6-3, 7-6(3), 6-1. Women: I Swiatek bt A Kontaveit 7-6(4), 6-0; M Kostyuk bt V Gracheva 6-1, 6-2; S Kenin bt J Pegula 4-6, 6-1, 6-4; B Krejcikova bt E Svitolina 6-3, 6-2; S Stephens bt K Muchova 6-3, 7-5