The world number one, the champion also in New York in 2010 and 2013, added the US title to the record 10th French Open he captured in June.
Old rival Roger Federer won the season's other two Slams at the Australian Open, beating Nadal in the final, and Wimbledon in an illustration of the two Grand Slam greats' enduring appeal and power.
Nadal's Grand Slam tally is just three behind Federer's record 19.
For Nadal, it was his fifth title of the year and 74th of his career while the $3.7 million (3.07 euros) winner's prize boosted his earnings to a shade under $90 million.
It was a desperately disappointing afternoon for Anderson, the world number 32 playing in his maiden Slam final at the 34th attempt.
He was the first South African in a US championship final since Cliff Drysdale in 1965 and was bidding to become his country's first Slam champion since Johan Kriek at the 1981 Australian Open.
The Johannesburg-born, Florida-based Anderson finished the 2hr 28min final with 40 unforced errors to Nadal's 11, failing even to carve out a single break point.
In a final guaranteed to result in the fifth Slam champion in succession who is 30 or older, Nadal was on top from the start.
He had 28th-seeded Anderson scrambling to save two break points in the third and fifth games before the Spaniard converted his fifth off a forehand error for a 4-3 lead.
The world number one held and broke again, cleverly forcing the 31-year-old South African out of position on set point after 58 minutes of action.
By the end of the opening set, Nadal had just five unforced errors to Anderson's 23 with the South African unable to muster a single break point.
The one-way traffic continued in the second set as Nadal broke for 4-2 off the back of three successive volleys.
Anderson even collected a time violation for his troubles as his efforts to compose himself failed horribly.
A brutal crosscourt forehand winner gave Nadal the second set 6-3.
Anderson was broken again in the opening game of the third set.
It was his fourth loss of serve in the final; before Sunday, he had been broken just five times in the entire tournament.
Anderson called the trainer for a bloodied right index finger after the fifth game, but his struggles continued.
He saved a match point but Nadal wrapped it up with a clinical backhand volley.