The 31-year-old Spaniard defeated South Africa's Kevin Anderson 6-3, 6-3, 6-4 for his third US Open title and his 16th career Grand Slam crown after having taken a 10th French Open trophy in June at Roland Garros.
The triumph moved Nadal three shy of Roger Federer's all-time record of 19 Slam singles titles.
Stephens thrashes Keys to win first US Open title
The US Open was the final Slam at which Toni, Nadal's long-time coach and inspiration, will join him, instead taking a role directing Nadal's youth academy.
In his victory speech, Nadal reflected on what Toni has meant to his life in building the grit to overcome numerous knee injuries.
"It's not one lesson. Diary is in the head from 3 years old," said Nadal. "Probably without him I'll never be playing tennis. I'm thankful I had somebody like him pushing me all the time. Because he gave me motivation I could get through all the problems I had in my career. I can only thank him for making me stronger."
Nadal, Federer march on in US Open
When Nadal reclaimed the world number one ranking last month, it was the first since in more than three years he had topped the list.
And when Federer lost in the US Open quarter-finals to Juan Martin del Potro, Nadal was ensured of keeping the top spot.
It has been a long journey for Nadal to his latest Grand Slam glory.
Nadal won an under-12 regional crown at age eight and by 12 had captured Spanish and European age-group junior titles.
By 15, he had turned professional and was facing such foes on the global circuit as Anderson, whereas at 17, he won his first match against Federer.
At 19, Nadal won the 2005 French Open in his debut, the first of nine Grand Slam titles in 10 years he would claim on the red clay of Roland Garros, cementing a legacy as the greatest player ever seen on the surface.
It was early in his career when Nadal began his habit of biting the championship trophies he wins.
Nadal added Wimbledon crowns in 2008 and 2010, an Australian Open title in 2009 and completed the career Grand Slam in 2010 by defeating Novak Djokovic in the US Open final, becoming the youngest in the Open era (since 1967) to complete the four-event career sweep.
And only Nadal and Andre Agassi can say they have a career Grand Slam and an Olympic men's singles gold medal, Nadal having claimed his in 2008 at Beijing.
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