Tsitsipas looked to be on course to become the first Greek major champion, but legendary top seed Djokovic produced a stirring fightback to win a thriller 6-7 (6-8) 2-6 6-3 6-2 6-4 at Roland Garros.
The indefatigable world number one etched his name in the record books on Court Philippe-Chatrier, becoming the first man in the Open Era - and only the third of all time - to triumph at each grand slam at least twice.
Djokovic had never won a major from two sets behind in a championship match but is just one shy of the record tally of 20 grand slam titles held by Roger Federer and Rafael Nadal, who he beat in an epic semi-final on Friday.
Tsitsipas appeared to be increasingly hampered by a hip injury as he endured heartbreak in his first grand slam final.
The 2016 champion won three service games without losing a point in a strong start on a sunny afternoon in Paris and there was relief when he picked himself up following a fall at speed while running at full tilt trying to retrieve return a deft drop shot.
A sprightly Tsitsipas was feeding off the energy of the crowd and had a set point after Djokovic skewed a forehand wide, but the 34-year-old showed the mentality of an all-time great to get himself out of a hole and broke in the next game when a stray forehand from the fifth seed put him 6-5 down.
Djokovic was clearly struggling with the sun in his eyes as he failed to serve out the set and Tsitsipas charged into a 4-0 lead in a brilliant tie-break, which he eventually won after saving a set point with a majestic forehand winner down the line.
Tsitsipas maintained the momentum, breaking in the opening game of the second set when Djokovic sent a forehand beyond the baseline and continuing to show rapid pace over the court.
The 22-year-old was relentless, returning superbly and unleashing a serious of glorious winners as he went a double break up before serving out the set in ruthless fashion.
Yet Djokovic hit back like he has done so many times over the years in the third set, taking a 3-1 lead by grasping his fifth break-point opportunity of a marathon game in which he put his opponent under huge pressure with a string of searing, precise returns.
The Serbian's forehand was firing on all cylinders as he sealed the set, then broke in the first game of the fourth and again to lead 3-0 with a sublime drop shot.
Tsitsipas' unforced error count was rising rapidly and he was not moving as freely, with the wind in Djokovic's sails as he levelled the match.
World number five Tsitsipas held after saving a break point in the first game of the decider but Djokovic was not to be denied a 2-1 lead, forcing an error as he continued to show astonishing staying power along with finesse and power.
Tsitsipas showed great fight but Djokovic served out a match of such high drama to get his hands on La Coupe des Mousquetaires once again.