The victory, his fourth in 10 Flushing Meadows finals, capped another remarkable Grand Slam campaign for Djokovic with wins at the Australian, French and US Opens and a return to the top of the world rankings when they are updated on Monday.
The Serb becomes the oldest US Open men’s winner in the Open Era and the first to win three Grand Slam events in a season for the fourth time.
The win was also measure of revenge for Djokovic.
The second seed walked out on to a packed Arthur Ashe Stadium on Sunday and stared across the net at Medvedev the man once again standing between him and history just as he had two years ago.
The last time the two clashed at the US Open was in the 2021 final, when the Russian captured his only major and denied the Serb a rare calendar Grand Slam.
Medvedev defeated Djokovic in straight sets in the 2021 final to prevent the Serbian from becoming the first man to win all four Grand Slams in the same year since Rod Laver in 1969.
Djokovic admitted to feeling overwhelmed on that occasion, but there were few senses of nerves as he quickly took command of Sunday's championship match.
The second seed burst out of the gate with a confident hold sealed by successive aces and struck at the first opportunity, punishing Medvedev for a double-fault to break for a 2-0 lead.
A third ace consolidated his advantage before Medvedev got on the board in the fourth game.
The pair traded holds largely untroubled until Djokovic again put pressure on Medvedev as the third seed served down 2-5.
Medvedev dug in to twice stave off set points, but Djokovic calmly made the set his the following game.
Medvedev dethroned last year's champion Carlos Alcaraz with a "12 out of 10" performance in the semi-finals, but he struggled to replicate his very best consistently against an imperious Djokovic.
Attempting to be the first player to beat the top two seeds en route to the title since 1975, Medvedev once more repeatedly found himself under the pump early in the second set.
He was able to resist, hitting a sweeping volley to fight off break point as he secured a gutsy hold for 4-3 before finally asking questions of Djokovic.
A leaping overhead gave Medvedev his first break chance of the contest the very next game, but Djokovic responded with a brilliant scoop on the half-volley to save it.
Djokovic wobbled serving at 5-6, double-faulting twice as Medvedev brought up set point. But Djokovic was waiting as Medvedev went cross-court, and put away the volley to force a tie-break.
Medvedev seemed to have the momentum on his side after winning an astonishing rally to nose 5-4 ahead only for Djokovic to bag the next three points, snatching a marathon 104-minute second set and closing in on a historic triumph.
Djokovic sportingly offered to help Medvedev to his feet after the Russian took an awkward tumble early in the third set, but there was no such goodwill when two break points came about soon after.
Medvedev pumped a backhand long to hand Djokovic a 3-1 advantage. He gave the break straight back, but Medvedev faltered again and there was no mistake second time around as Djokovic wrapped up the title before the emotions started to pour out.
