The defending champion had beaten Fritz in all eight of their previous meetings, including a five-set win at Melbourne Park in 2021 and a crushing victory at the US Open last year.
But Djokovic has taken his time to get going at this year's tournament as he seeks an 11th title and 25th major to surpass Margaret Court's haul, and the top-seeded Serb was unable to break in a marathon first game that had nine deuces.
Fritz saved eight break points and went toe to toe with his opponent in energy-sapping conditions before setting up two set points but Djokovic saved them both to force a tiebreak, where he took his level up a few notches.
The Serb cupped his ear as the crowd roared when he fired a superb cross-court winner to earn five set points and bagged the early lead in the contest after 84 minutes.
Fritz broke early in the next set and bailed himself out of trouble several times with stinging backhand winners as Djokovic looked to respond, but the American held firm and drew level at one set all with a comfortable hold.
Djokovic cooled off by placing ice packs on his head in the third set but he was only comfortable after finally breaking his opponent on his 16th attempt en route to a 2-0 lead, which gave him the platform to push on and win the set.
Fritz appeared to struggle with his movement at times in the fourth set and Djokovic moved in for the kill to break in the sixth game before fending off a comeback attempt from Fritz to prevail.
"It was extremely hot when the sun was still out there," Djokovic said after the match at Rod Laver Arena, which stretched to three hours and 45 minutes.
"Physically and emotionally very draining. Huge round of applause to Fritz for a great performance today and this tournament.
"Conversion of the break points was really poor, but I think at the end of the day I managed to break him when it really mattered, the third and the fourth."
The win was Djokovic's 33rd consecutive victory in Melbourne, a startling run stretching back to 2018. He did not compete at the event in 2022 due to his coronavirus vaccination status.
