Nadal is the defending champion of the US Open and beat Djokovic in that final.
However this year, Djokovic has had the upper hand against the Spaniard and is 5-0 against Nadal this season, with all those matches being finals, including this year's Wimbledon.
With a win, Djokovic will become the seventh man to win three Grand Slam titles in a calendar year. A victory for Nadal would give him his second consecutive US Open crown and an 11th Grand Slam title.
Let's look at 10 things you need to know about this final.
Novak Djokovic lost in the US Open final last year to Rafael Nadal and just couldn't seem to figure out how to beat the Spaniard.
This season has been a different story. Djokovic is 5-0 against Nadal this season, with all of those matches coming in finals of tournaments.
One of those finals was the Wimbledon finale in June, a match that gave Djokovic his second Grand Slam title this season.
Novak Djokovic is trying to become the seventh player in the history of men's tennis to win three Grand Slam titles in a single season.
Djokovic won the Australian Open in January against Andy Murray and followed up a disappointing French Open performance with a dominant run at Wimbledon, where he beat Rafael Nadal in the final.
With a win against Nadal at the US Open final on Monday, he will join a select group of tennis legends who've dominated for an entire year.
Rafael Nadal won the 2010 US Open over Novak Djokovic, and he'll have a chance to replicate that Monday.
Last year's Open triumph was Nadal's ninth Grand Slam win and the only time's he won the US Open.
A victory over Djokovic would give Nadal his second Grand Slam title of 2011; he won the French Open this past June.
Rafael Nadal survived a very good start to the semifinals against Great Britain's Andy Murray and dominated him through four sets for a place in the US Open final.
Nadal had very good quickness, and his serve was solid as well. Hard courts like the ones at the US Open aren't Nadal's strength, but he has become increasingly better on the surface the past few years, highlighted by his wins at the Australian Open in 2009 and last year's US Open.
The US Open has been interrupted by rain this year, and it has messed with the schedule a bit. Rain has cut into a few days of play over the last few weeks, causing the men's final to be played on Monday.
Roger Federer would prefer that the men's finalists have a day of rest between the semifinals and final. This year Djokovic and Nadal will get a day of unplanned rest due to the rain, but that is not the norm.
The unique "Super Saturday" on the final weekend of the US Open features the men's semifinals and women's finals on Saturday, with the men's final on Sunday not being the way Federer would prefer the tournament be played.
"The Super Saturday I think is just not feasible," Federer said, referring to the normal television-driven Open schedule.
"I'm sure that there have been many finals played here where one player had a huge advantage and I don't think that should be happening before such a huge match here. I just don't think Saturday/Sunday is feasible any longer."
The Super Saturday idea, along with the men's final on Sunday is the best way the television networks think they can get the best ratings, even if the players aren't in agreement.
Djokovic also was not pleased with the rain and scheduling, saying in an LA Times article: "It's just too much, really. It's too much."
Djokovic criticized the organizers for not having roofs or covers for the courts.
"There are some things that I don't understand," he said. "I really hope people will strongly reconsider."
Novak Djokovic is playing some of his best tennis of his life right now and has shown as much mental strength as he has physical strength during this US Open run.
Djokovic battled through two match points for Roger Federer during the semifinals and showed great poise and skill to beat the 16-time Grand Slam champion.
Djokovic does not get mentally beaten anymore, which is a sign of his maturity. Unforced errors and bad starts to matches don't bother him as much as they used to, and this has helped him remain calm and composed throughout his tennis.
Novak Djokovic is battling a bit of fatigue coming into the US Open final against Rafael Nadal after having to overcome a two-set deficit to Roger Federer in the semifinals on Saturday.
Djokovic was hindered by a shoulder injury a few weeks prior to the US Open, but so far in New York it has not been a factor in his play and hasn't seemed to bother him a bit.
Rafael Nadal has dropped only one set on his road to the 2011 US Open final, and that's an impressive feat against any level of competition.
But Nadal has gone on this near-perfect run against the game's best players, making the feat even more memorable.
Nadal has beaten Andy Murray, Andy Roddick, Gilles Miller and David Nalbandian to set up a match with Djokovic in the final.
Rafael Nadal used to be the No. 1 ranked player by the ATP, but that crown belongs to Novak Djokovic, who cemented that ranking after his win at Wimbledon earlier this year.
Nadal will be looking to prove he's still the best player in the world during Monday's US Open final. A win on Monday would give him his second Grand Slam crown of the year.
If Nadal wins on Monday, he will regain some of the aura of invincibility he started to build over the past two to three years.
Novak Djokovic and Rafael Nadal will play an exciting US Open final on Monday, and history will be on the line.
Nadal will try to win his second straight US Open crown, while Djokovic will attempt to be the seventh player ever to win three Grand Slam tournaments in a season.
The US Open has seen some great matches this year, and this final will be a fitting end to the year's last Grand Slam event.
There's nothing better than watching two of the game's best players battle with the US Open title on the line.