The Serb, who was playing his first singles match since the Davis Cup six weeks ago, has strengthened his grip at the top of the rankings, taking a 580-point lead over Spain's Carlos Alcaraz, who exited the tournament on Tuesday.
The 24-time Grand Slam winner made only nine unforced errors and did not drop serve throughout the match as he beat the Argentine world number 31 in one hour and 23 minutes.
"I am pleased ... Some parts of the match were really good, others losing the rhythm. But I think it is normal to be rusty a little bit after not playing an official match for so long," Djokovic said.
He will next play Dutchman Tallon Griekspoor.
World number three Daniil Medvedev lost to Bulgarian Grigor Dimitrov 6-3, 6-7(4), 7-6(2).
The Russian denied making an obscene gesture towards the crowd, who had booed him earlier, after losing a heated second-round clash.
Medvedev walked off the court at the end of the match examining his hand before pointing his middle finger at the stands.
Greek seventh seed Stefanos Tsitsipas beat Canadian Felix Auger-Aliassime 6-3, 7-6(4) and will next face Alexander Zverev after the German dug deep to beat Frenchman Ugo Humbert 6-4, 6-7(3), 7-6(5).
American Tommy Paul's hopes of making the ATP Finals ended when the 12th seed lost to qualifier Botic Van de Zandschulp 6-4, 2-6, 6-3, while 13th seed Alex de Minaur of Australia remained in contention for a spot at the tournament in Turin by beating Dusan Lajovic 4-6, 6-4, 6-4.
Francisco Cerundolo stunned Norwegian Casper Ruud 7-5, 6-4. The Argentine will next play 11th seed Hubert Hurkacz of Poland, who earlier beat Roberto Bautista Agut 6-3, 6-2 in less than an hour.
In the final match of the day, sixth seed Holger Rune eased past Dominic Thiem 6-4, 6-2. The Dane will next face Daniel Altmaier who progressed past Taylor Fritz on a walkover.
