Both Nadal and Djokovic took some time off after the Australian Open, where Djokovic claimed a record-extending ninth title in February.
Facing a stern test against Sinner, the top-ranked Djokovic eased into his clay-court routine to reach the third round and improve his unbeaten record this season to 10-0.
"It was a very good encounter. I thought it was a great first match, a big challenge for me," said Djokovic, who is a Monaco resident. "I just hung in there today and managed to find the right shots and the right game at the right time."
After dropping his serve early, Djokovic won four straight games.
Sinner, who arrived in Monte Carlo following a runner-up finish in Miami, saved two match points but was too often troubled by Djokovic's mix of baseline attacks and subtle drop shots. The 19-year-old Sinner bowed out on a double-fault.
Djokovic, who beat Nadal in the 2013 final and won the tournament again in 2015, could face the Spaniard in Sunday's final.
Against Delbonis, an Argentine qualifier, Nadal saved four of the five break points he faced. He will take on Grigor Dimitrov in the next round.
The Monte Carlo Masters is back on the calendar with no fans after it was canceled last year because of the coronavirus pandemic.