With the remainder of the first round matches to be played tomorrow, the second round opponents for world number one Rafael Nadal of Spain, Roger Federer of Switzerland and Alexander Zverev of Germany are yet to be decided.
The Spaniard is playing his first match since retiring with a knee injury in the semis of the US Open nearly two months ago, so will be fresh, even if his fitness is untested in the heat of competition.
The 31-year-old Djokovic will become the first player to be ranked outside the Top 20 then climb to No. 1 in the same season since Marat Safin in 2000.
At this point in the tournament in Paris, Djokovic has reached the third round, where they will play against Bosnian Damir Jumhuri.
"I felt better than I thought I would one week ago but in the last few days I started to feel a bit in my abdominal, especially when I was serving", said the 17-time grand slam victor.
"I didn't want to play there at that time".
Khachanov, who won the Kremlin Cup in Moscow last month, did not face a break point in the 2 1/2-hour match.
Djokovic arrived in Paris knowing that he would regain the top spot he relinquished two years ago if he bettered the Spaniard's performance at the indoor event he has won four times. But his record in Paris-Bercy is not great-the third round last year-and he has a tough opener in the shape of Lucas Pouille or Gilles Simon. But in the past few days, I started to feel a little bit [of an] abdominal [injury], especially when I was serving. That gave No. 13 seed Fabio Fognini of Italy a walkover.
"In both the US Open and Shanghai, I've played as good as ever", said Djokovic, who claimed his 14th major championship in NY. But Dzumhur pulled out with a back problem before the match could be completed, trailing 6-1, 2-1 at the time. It was me today.
Djokovic, looking in much sharper form than his opening match against Joao Sousa, took the set in 39 minutes.
There was a more stressful passage for Isner, but the American did just enough to edge out Mikhail Kukushkin 6-3 6-7 (2-7) 7-6 (7-1) and keep his hopes of an ATP Finals place alive.
There may be an element of the precautionary with his, as the ATP Tour Finals begin in less than two weeks.
Cilic, the fifth seed, secured his quarter-final ticket with a 7-6 (7/5), 6-4 victory over Grigor Dimitrov.