The Argentine competed in his first Grand Slam final in nine years after the last time he reached a summit clash was back in 2009 when he had defeated Federer to win the title at the Flushing Meadows.
But Djokovic is almost six years younger than Federer and - prior to a two-year barren spell that was ended by his Wimbledon triumph - had been winning slams at an average of almost two a season.
The Serbian has completed a remarkable comeback from injury and after winning at Wimbeledon earlier in the year he has won back-to-back Grand Slams for the first time since 2016.
While many hope del Potro gets that second major someday, including Djokovic - he is severely owed by the tennis gods - his foe was simply too good in the opening set. However, Djokovic had a slightly better percentage (15-for-19) and converted on his only break point opportunity to secure the set.
Nishikori's only real chance came at the start of the second set when, having survived a long game on his own serve, he had two chances to break the Djokovic serve - his only break points of the match.
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.
Early in the tournament the extreme heat and humid conditions in NY were clearly troubling Djokovic.
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 playing nearly at the limit, all the time, looking for winners with my forehands, backhands, and I couldn't make it", del Potro said, "because Novak (was) there every time".
Djokovic, who struggled with the NY humidity in the first two rounds, did not drop a set from the third round onwards.
That is despite winning fewer Grand Slams - the most lucrative tournaments in tennis - and fewer ATP Tour titles than Swiss great Roger Federer. "I'm sad because I lose but I'm happy for Novak". In terms of results, I played finals of Queen's, won Wimbledon, won Cincinnati, and won US Open.
It was after watching Pete Sampras win Wimbledon - while sitting in his parents' pizza parlour as a six-year-old - that Djokovic decided tennis was the sport for him.
'I think we have pushed each other to the limit every time we get to play each other.
Same goes for the Big 3 of today (with all due respect to Andy Murray, he of the three majors plus two Olympic singles gold medals, it really isn't a Big 4). "It's a Grand Slam final!"
Backed by his singing boys, Del Potro roared back in the set by breaking Djokovic to go back on serve.
In the category that it doesn't matter how old one is, but rather how young they feel and can perform, the 31-year-old Djokovic is the ninth consecutive player over-30 to win the men's title at a Slam.
But he had a 4-14 losing record against Djokovic, including four at the Slams - two of them at the US Open in 2007 and 2012.