Bruno Soares of Brazil and Mate Pavic of Croatia beat the 32-year-old Serbian star and his countryman Filip Krajinovic 6-2, 4-6, 10-4 to progress to the quarter-finals.
The doubles experts survived Djokovic’s powerful serves with crisp volleying as their quick court coverage overwhelmed the Serbian pair’s bold shots.
Top seed Djokovic will make his Japan Open singles debut later this week playing Alexei Popyrin, a 20-year-old Australian, at the Ariake Coliseum, a venue for the Tokyo 2020 Olympics.
His main challengers in the Japan event will be second seed Borna Coric of Croatia and Belgian third seed David Goffin.
Earlier this month, Djokovic was forced to pull out of his US Open fourth-round clash with Stan Wawrinka due to a nagging injury in his left shoulder.
His return means he could play out the season and hold off a challenge to his number one ranking from US Open winner Rafael Nadal.
Later in the day, 2014 US Open champion Marin Cilic of Croatia will face Yuichi Sugita, entering on a wild card, who leads local hope after Japanese star Kei Nishikori pulled out of the tournament due to injuries.