The Serbian, who will return to world number one next week, was 6-1, 2-1 up when a back injury got the better of his Bosnian opponent.
Djokovic's return to No 1 when the new ATP rankings are released next Monday was sealed on Wednesday when the current holder of that accolade, Rafa Nadal, had to pull out of the Paris event with an abdominal injury.
"Reflecting on what I've been through in the previous year, it's quite a phenomenal achievement", said Djokovic, who won Grand Slam titles at Wimbledon and the US Open this summer. "Of course I am not happy, but I have to accept it and stay positive".
The 37-year-old Swiss had only made a late decision to compete in Bercy after winning his 99th title in his home town Basel on Sunday but, despite a touch of raggedness, was sharp enough on Thursday to outclass the Italian 6-4 6-3 in his opening match.
Djokovic's 20th consecutive win sets up a last-eight clash with Marin Cilic.
Elsewhere today, Switzerland's Roger Federer, the 2011 victor, made it through without hitting a ball at the AccorHotels Arena.
It's one of the best sets I have played this year I would say.
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Cilic fired 29 winners to advance to the last eight in the French capital for the third straight year.
The Paris tournament is the last before the season-ending ATP Finals in London, which begin on November 12.
"I am very close to London, to securing my spot mathematically", said Cilic, who is part of the Croatia team facing France in the Davis Cup final at the end of this month.
Djokovic, who is looking to win his 33rd ATP World Tour Masters 1000 crown this week in the French capital, will return to the summit of men's professional tennis on Monday nearly two years to the day since he completed his 223rd and most recent week in top spot.
In other matches today, American defending champion Jack Sock progressed to round three.
Serbia's Novak Djokovic celebrates after winning his men's singles second round match against Portugal's Joao Sousa, on day two of the ATP World Tour Masters 1000 - Rolex Paris Masters - indoor tennis tournament at The AccorHotels Arena in Paris, on October 30, 2018.
In the quarter-finals, Khachanov will meet Germany's fourth seed Alexander Zverev, who took 80 minutes to overpower and finally subdue the scurrying defiance of Argentina's Diego Schwartzman 6-4, 6-2.