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.
"But if Novak Djokovic wins this US Open he will equal Pete Sampras's tally of 14".
Rendered ineffective for years due to wrist issues, del Potro made his first Grand Slam final since that win over Roger Federer almost a decade ago.
Djokovic, who was seeded sixth, is one of only eight men to win the Wimbledon-US Open double and has now accomplished that feat for a third time.
To his credit, Del Potro rallied again to recover a break in the third set, but Djokovic was simply too good and sealed the match with a smash before collapsing in delight.
After taking just two points off Del Potro's first three service games, Djokovic, in his 23rd final at the majors, pounced to break for 5-3.
Djokovic, who has made seven previous finals in NY but won only two, will now face Del Potro in Sunday's final.
This follows a two-year Slam drought for the 31-year-old Serb, who suddenly is tied with Pete Sampras for the third-most major trophies by a man, trailing only Roger Federer's 20 and Rafael Nadal's 17.
However, the underdog dialled up his intensity to great effect - that massive forehand clicking into gear - and was aided by significant crowd support as he capitalized on a brief dip in Djokovic's form to get back on level terms.
Djokovic has only ever lost one match from more than 200 when he has led by two sets - to Austria's Jurgen Melzer at the 2010 French Open - but there was no sign of that happening again.
"I was sad for Serena because she's a great champion", del Potro said. Ahead of this match, he had a return percentage of 82 per cent, the most by any US Open competitor this year.
But he is a strong candidate for any title when he is fit and the fact he has the most number of victories by anyone over world number one player just goes to show how risky he can become when he is without any injury.
ESPN's presentation of the US Open Women's Championship - Naomi Osaka, just 20, shocking the legendary Serena Williams 6-2, 6-4 with action on and off the court as controversy engulfed the second set - posted a 2.5 rating for the match itself and a 2.4 for the full three-hour telecast.
"I was very disappointed with my performance that day".
After she was given a code violation for coaching in the second game of the second set by Ramos, a fuming Williams told the umpire that she "never cheated" and "would rather lose" than do that. It's unbelievable. I don't feel sad that I couldn't win grand slams because of them. I think we have pushed each other to the limit every time we get to play each other. "He has 14 (Grand Slams) already".
Pressure was on all three to win the last Grand Slam of the year last week with Federer winning the Australian Open, Nadal the French Open, and Djokovic triumphing at Wimbledon. He can also take aim at trying to finish the season at No. 1, something he did in 2011, 2012, 2014 and 2015.
However, the night didn't end up being about the 20-year-old champion.
There may have been no game more important to Djokovic's win or simply entertaining than the eighth game of the second set.