As 40,000 fans watched Paris St Germain's Champions League final on video screens across the road at the Parc des Princes, the 38-year-old turned on the style on Court Philippe Chatrier.
Three-time champion Djokovic, bidding for a historic 25th Grand Slam title, was given a thorough workout at times by his 23-year-old opponent but more than matched Misolic's power and always looked in complete control.
Djokovic failed to convert nine break points early on but made the breakthrough for a 4-2 lead after showing incredible defensive skills to retrieve a barrage of smashes.
The Serb saved a break point at 1-2 in the second set and then earned applause from the fans as he sportingly dusted his opponent down after Misolic tumbled over and got his sweat-soaked shirt coated in clay.
He soon showed his ruthless side though to break serve with a backhand winner as he raced into a two-set lead.
The sixth seed was in no mood for a late night as exploding fireworks and roars rang out from across the road and the third set followed the same pattern as the first two as he cruised through to a last-16 clash against Britain's Cameron Norrie.