Djokovic, 31 years old, overwhelmed Juan Martín del Potro, 29, in an entertaining-and sometimes intense-U.S.
Djokovic, meanwhile, claimed his second major of the year after winning Wimbledon in July and draws level on Pete Sampras with 14 career successes as a result.
He has dropped just one set in getting to the final, and will be roared on by a vocal support base that will make the Big Apple feel like Buenos Aires tonight.
Playing on the same court where Sampras claimed the last of his 14 slams, Djokovic has endured more disappointment than joy in Arthur Ashe Stadium, losing five finals.
Like the victorious Djokovic, Del Potro has had to overcome injury problems to get back to this stage.
In the immediate aftermath of Djokovic's victory, he embraced del Potro at the net in a heartwarming show of class and respect between the friends and foes. But del Potro broke back, then held at love and had chances for another break on his next opportunity before Djokovic finally held to end a 22-point game that lasted more than 20 minutes.
He made no mistake in seeing it out and strolled into a one-set lead after 42 minutes.
Twelve months ago, Novak Djokovic wasn't even playing in the US Open while trying rehab a nagging elbow injury that eventually required surgery.
Del Potro, the No. 3 seed from Argentina, advanced in Friday's other semifinal when defending champion Rafael Nadal retired from their semifinal because of a painful right knee after dropping the opening two sets.
In their first meeting in a Grand Slam final it was Del Potro, back at this stage for the first time since 2009, who won the coin toss and elected to receive under the Arthur Ashe Stadium roof with heavy rain falling in NY.
Britain's Alison Hughes, the second woman to umpire a U.S. Open men's singles final, kept a low profile as the two former champions went to work.
However, the despair on Sunday belonged to a teary del Potro, who was back in a grand slam final for the first time since his one and only title in NY in 2009.