Medvedev defeated Djokovic in straight sets two years ago to prevent the Serbian from becoming the first man to win all four Grand Slams in the same year since Australian great Rod Laver in 1969.
On Sunday the 36-year-old Djokovic goes in search of a record-equalling 24th Grand Slam singles title against Medvedev, who unseated reigning champion Carlos Alcaraz in a gripping semifinal.
Djokovic will return to world No 1 next week, but he is wary of being swept up by the significance of the occasion in New York.
"Every time in a Grand Slam final it's another shot for history, you know, and I'm aware of it, and of course I'm very proud of it," said Djokovic.
"But again, I don't have much time nor do I allow myself to reflect on these things or think about the history too much in this sense.
"Because when I did that in the past, like, '21 finals here I was maybe overwhelmed with the occasion and the opportunity and I underperformed.
"So I don't want this to happen again."
Djokovic fell agonisingly short of matching Margaret Court's all-time mark for most Grand Slam singles titles when he lost to Alcaraz in five sets in the Wimbledon final in July.
That remains his only defeat at the majors since a quarterfinal loss to Rafael Nadal at the 2022 French Open. He is 33-1 at the Slams since then.
Djokovic is the first man in the Open era to play in 10 finals at two different Grand Slams. He has a perfect record at the Australian Open, but New York is the site of some of his biggest disappointments.
'AGE IS JUST A NUMBER'
He is just 3-6 in US Open finals but could become its oldest men's champion in the modern era, surpassing Australia's Ken Rosewall who was 35 when he won in 1970.
"Physically I have been as fit or as prepared, as strong as, I don't want to say as ever, but, I mean, as good as I have been in years and years," said Djokovic, who swept past 20-year-old Ben Shelton in the last four.
"Age is just a number, that phrase is resonating at the moment with me. And, you know, I don't want to even consider leaving tennis or thinking about an end if I'm still at the top of the game.
"I just don't see a reason for that."
Medvedev avenged his Wimbledon semifinal whipping by Alcaraz to reach his fifth Grand Slam final.
The 27-year-old Russian lost a five-set classic to Rafael Nadal here in 2019. He was also beaten by Djokovic in Melbourne two years later before going down to Nadal at the following Australian Open.
"If I lose on Sunday, the tournament, it's like it's a good tournament but I'm going to be hell of a disappointed. That's how tennis is," said Medvedev.
Djokovic leads the head-to-head 9-5 but Medvedev knows his rival wants to set the record straight after the 2021 final defeat which left him in tears.
"I think the only way I can use it is, as I say, thinking that Novak, when he loses, he's never the same after," said Medvedev.
"So he's different. It's just a different mentality. That's why he has 23 Grand Slams, whatever, Masters 1000s, weeks at No 1."
"So I have to use it knowing that he's going to be 10 times better than he was that day. And I have to be, if I want to still beat him, 10 times better than I was that day."
Medvedev has already torn up the script once this tournament with a "12 out of 10" performance against Alcaraz. He may need another off-the-charts display to deny Djokovic one more time.
"Novak is going to be his best version on Sunday, and I have to be the best-ever version of myself if I want to try to beat him."
