Federer's latest near-miss will inevitably again raise questions about whether the father of four and arguably the game's greatest ever player will win another slam.
While Federer has managed just one grand slam crown in almost six years, Djokovic has now amassed nine in that time.
One more and Djokovic will join legends Rod Laver and Bjorn Borg with 11 majors such is the Serb's growing standing among the pantheon of greats.
Only Federer (17), Rafael Nadal (14), Pete Sampras (14) and Roy Emerson (12) have accrued more.
The tennis titans had to endure a three-hour rain delay before resuming world sport's most compelling individual rivalry finally, which is now also the most enduring in men's grand slam history.
Sunday's was their 14th meeting at the majors and 42nd overall and Djokovic's success squared his career series with Federer at 21 wins apiece as Federer was unable to defy the doubters and father time.
Both players entered the showpiece final in sublime form.
Djokovic qualified for all four grand slam deciders in a season for the first time with a record-setting semi-final rout of defending champion Marin Cilic.
Federer had swept 28 straight sets since Wimbledon.
But just like their high-stakes showdown at the All England Club, Federer was slow to find his A-game.
After dropping serve only twice all tournament, Federer was under the pump from the get-go. The five-times champion - featuring in his first final in New York in six years and an unprecedented 28th grand slam title match in all - had to fend off two break points in the opening game and then dropped serve to fall behind 3-2.
He struck back immediately with a net-rush to wrong-footing Djokovic and send the Serb tumbling into the court.
Djokovic carried on with a grazed knee and elbow and claimed a second break in the seventh game as Federer's unforced errors continued to cost him.
His mistake rate rose to 15 as Djokovic snared the scrappy opening set on a backhand miss from the second seed.
Federer introduced his SABR - the so-called Sneak Attack By Roger - with instant success early in the second set. Storming the net on Djokovic's second serve, the daring Swiss whipped a backhand and then rifled another down the line to have the world No.1 staring down triple break point at 1-0 and love-40.
"If he wins this, it will be the shot of the last five years that he's come up with. It's unreal," former world No.1 John McEnroe marvelled on US TV.
But once again proving himself the best defender in the game, Djokovic fought off a total of five break points to hold for 1-1.
Federer's next opportunities came in an epic ninth game when he garnered two set points, only to net a backhand return and then drive a relatively routine - by his supreme standards - forehand overhead long.
Djokovic finally held after a 20-point game - but he couldn't hang on a second time when Federer converted his third set point with a probing backhand cross-court that again had the Serb spread-eagled.
The thunderous applause almost raised the half-finished roof at Ashe and Federer continued the assault early in the third set.
The SABR ploy seemed to unsettle Djokovic.
But out of nowhere Federer gifted the top seed a service break from 40-15 up in the third game.
After a strong overrule from Eva Asderaki, the first women's chair umpire to control a men's US Open final, earned Federer a break-back point before Djokovic obliged by dumping a forehand into the net.
Federer rued missing two more break-point chances in the eighth game after dropping serve once more from 40-15 to allow Djokovic to close out the set for a two-sets-to-one advantage.
There was no coming back for Federer when he was broken early in the fourth set, and then again for a sixth time, as Djokovic stayed cool to stave off three break points and serve out the final after three hours and 20 minutes.
