With the win now, Djokovic has extended his head-to-head record against Del Potro to 15-4 as the Argentine was unable to upstage the Serb.
Amid increasing noise between points and serves, which prompted frequent interventions from chair umpire Alison Hughes, the previously assured Djokovic - who missed the tournament a year ago due to an elbow injury - appeared agitated.
It comes seven years after the New York Times revealed top chair umpires were skipping the US Open because of how poorly it paid officials.
Del Potro cracked first when serving in the eighth game of the first set.
AS with any final weekend of a grand slam there was plenty of cash being dished out at the US Open the past couple of days.
But against one of the best returners in the business, Del Potro needed to be far more assertive.
Djokovic's most hard opponent this tournament has been the heat and humidity, so Sunday's cool and wet conditions, resulting in the roof being shut on Arthur Ashe Stadium, were perfectly to his liking.
Millman will move into the world's top 40 for the first time in his career following his success on court in NY.
The disappointment on Sunday belonged to a teary Del Potro who was back in a Grand Slam final for the first time since the big Argentine won his one and only title at Flushing Meadows in 2009.
"You've got to make decisions really quick and I thought I played really, really well".
There are other important statistics to consider, however, which clearly suggest that brain will play as significant a part as brawn on Sunday. Both of them displayed their dominant self early on to exchange honours. From there Djokovic comfortably served out the set.
Djokovic won a tiebreaker to take the 95-minute second set.
Djokovic captured the first of his 12 majors in Melbourne in 2008, but it was three years before he added his second.
"I want to say Pete, I love you, you're my idol", said Djokovic of Sampras.
Coming after his triumphant return at Wimbledon in July, the latest success is evidence enough that technically, tactically and physically Djokovic is back to his best.
When it ended, thanks to a three-game closing run by Djokovic, he flung his racket away and landed on his back, arms and legs spread wide. This shows the current state of affairs in the women's tennis world that there is no absolute queen.
Djokovic's coach, Marian Vajda, called that moment the match's "turning point, obviously". That Williams lost a point, then a game, and was fined $17,000 are what will be remembered about that final. "(His) decisions were in accordance with the relevant rules and were re-affirmed by the US Open's decision to fine Serena Williams for the three offences".
But he struggled against the Top 2 players in the ATP Rankings, going 0-7.
After taking just two points off Del Potro's first three service games, Djokovic pounced to break for 5-3. That inspired me to start playing tennis.
The noise levels inside the Arthur Ashe Stadium was deafening as Djokovic and Del Potro got the crowd roaring with their display on-court. While del Potro put up a tough fight, the native of Serbia found a way to gut it out in the end.
Djokovic sprinted into a 3-1 lead in the third set before a battling Del Potro clung on, hitting back for 3-3.
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