The 31-year-old Spaniard, who captured a 10th Roland Garros in June and was runner-up to Roger Federer at the Australian Open in January, is the overwhelming favourite.
He is the world number one playing in his 23rd Slam final and who won his first major as a 19-year-old at the sixth attempt.
Anderson, two weeks older, is playing in his first final at the Slams after a career stretching 32 majors.
Nadal’s 73 career titles also dwarf Anderson’s modest three.
But the Spaniard is wary of the challenge posed by 6ft 8in (2.02m) Anderson’s deadly serve.
At the US Open, the South African has fired 114 aces and has been broken just five times in 108 service games.
He has also unleashed the tournament’s third fastest serve of 137 mph (220.4km/h).
“It’s a very tough one. He’s a huge player with an unbelievable serve and he plays so well on these kinds of surfaces,” said Nadal of a player he has known since he was 12 years old.
“I need to be ready for it. It is probably the most important match for me that remains this year, so I am going to try my best to play my best.”
Nadal was champion in New York in 2010 and 2013 while finishing runner-up in 2011.
He was expected to have been pushed hard by 2009 champion Juan Martin del Potro, who knocked out Federer in the last eight, when they met in Friday’s semi-finals.
But after being out-fought and out-thought in the first set, Nadal switched up his tactics, had the weary Del Potro scrambling around the Arthur Ashe Stadium court and eventually claimed a 15th successive semi-final win at the Slams.
Victory on Sunday would take Nadal to within three majors of Federer’s record of 19 and extend the iron grip of Nadal, Federer, Novak Djokovic, Andy Murray and Stan Wawrinka.
Since Federer won his first Wimbledon in 2003, an incredible 52 of the 57 Slams have been claimed by the five men.
– ‘Greatest competitor’ –
However, with former winners Djokovic, Murray and 2016 champion Wawrinka all not playing this year, opportunity has knocked for Anderson.
“We are accustomed to the few guys doing well, exceptional consistency. It’s tough beating those guys because they have had so much experience at this level,” said the world number 32.
“Even with them out, there have still been a lot of challenges I’ve had to face throughout this week. I have faced some of the best tennis players in the world.”
Anderson is 0-4 against Nadal, losing their most recent clash in Barcelona this year as the Spaniard swept regally through the European clay court swing.
In those four meetings, the Johannesburg-born Florida-based Anderson has claimed just one set.
In the pair’s only clash at the Slams, Nadal won in straight sets in the Australian Open fourth round in 2015.
“Nadal is one of the greatest competitors in sports, period. He’s an amazing fighter,” said Anderson, the first South African in the US Open final since Cliff Drysdale in 1965.
Johan Kriek remains the last Slam champion from the country, winning the 1981 Australian Open.
“Nadal really controls the court well,” Anderson said. “I really need to be dominant and control proceedings as much as possible, because if you let him do it, it’s very difficult.”
Sunday will be also an emotional occasion for Nadal’s coach since childhood, his uncle Toni, who will retire from life on the road at year’s end to devote himself to his nephew’s academy in Mallorca.
“He lives 300 meters from my house. I train at the academy. He is my uncle and he will continue to give me advice, but he has the right to do what makes him happy,” said Nadal.
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