Serbia’s Djokovic started strongly and dug deep in the second set on his way to a 6-3 7-6 (7-4) 7-6 (7-5) victory.
The 35-year-old, who draws level with Rafael Nadal in major wins, will return to the world number one ranking.
Greece’s Tsitsipas, 24, continues his wait for a first Grand Slam triumph.
“I have to say this has been one of the most challenging tournaments I have ever played in my life considering the circumstances, not playing last year, coming back this year,” said Djokovic.
“I try to pinch myself and really live through these moments. It’s a long journey. Only the team and the family knows what we have been through in the last four or five weeks.
“I would say this is probably the biggest victory of my life, considering those circumstances.”
Tsitsipas lost to Djokovic in his first major final at the 2021 French Open after relinquishing a two-set lead but, this time in Melbourne, he was always chasing the match.
In the few precious opportunities he had to threaten Djokovic – notably a set point to level the match at one set all – the third seed was unable to take them.
Djokovic has not lost at Melbourne Park since 2018 – a streak spanning a record 28 matches in the men’s singles.
He has regained the crown which he was unable to defend last year after being deported from Australia following a row over his Covid-19 vaccination status.