Del Potro will now face Djokovic, the 2011 and 2015 victor, who reached his eighth final at the tournament and 23rd of his Grand Slam career with a 6-3, 6-4, 6-2 stroll past Japan's Kei Nishikori.
The victory will also see Djokovic rise to No.3 in the world behind Nadal and Federer - the rankings again reflecting the "Big Three" status they have shared for so long.
Argentine third seed Del Potro had been seeking first Grand Slam title since 2009.
Djokovic also leads Del Potro 14-4 in their head-to-head encounters. But then he was broken in his next game.
This year, del Potro won his maiden ATP Masters 1000 title in Indian Wells - beating Federer again - made his second Roland Garros semifinal and posted his best Wimbledon result (quarterfinal) since 2013.
All that frustration was washed away when he struck the overhead victor to clinch victory over Del Potro, Djokovic falling to his back, arms and legs spread savouring the moment.
Djokovic's year got off to a less-than-ideal start, the Serbian set off on a five-day hike in the French Alps that proved transformative.
Novak Djokovic, of Serbia, celebrates after defeating Juan Martin del Potro, of Argentina.
Tilden won his first two grand slam titles in 1920 - including his first of seven US Opens.
'I think that was one of the most important, so to say, moments and periods of my life, my tennis career, my development.
He was asked how he had turned his poor early form this year into a dominant sequence of 26 wins from 28 matches, and climbed back from a low point of No 22 in the world to No 3. "I watched him win one of his first Wimbledon championships, and I grew up playing and thinking that one day I'll be able to do what he does", Djokovic said.
ESPN drew the joint second-highest TV audience they have ever had for the US Open for her final loss to Naomi Osaka, tied with the final between Djokovic and Roger Federer in 2015.
Nadal hobbled out of a semi-final match against Del Potro after two sets.
"I've been during all my career learning with Novak, Roger, Rafa, seeing them winning these events very often". "It's a Grand Slam final!"
"I was playing nearly at the limit all the time, looking for winners with my forehands, backhands, and I couldn't make it because Novak were there every time".
However, the odds were stacked against the 29-year-old journeyman took on the sixth seed Djokovic for a spot in the semi-finals on Thursday.
Four easy holds later and it was onto a tiebreaker that decided the second set, and ultimately the course of the match as Djokovic capitalised on several bad errors from his opponent to win it 7-4. He recouped the service break in the fifth game, but after holding serve, Djokovic went onto win the final three games of the over three-hour encounter.