Thiem is also the first to ever come back from two sets down in a US Open singles final to win, and the first men's Grand Slam champion who was born in the 1990s.
He became the first man in 71 years - since Pancho Gonzales in 1949 - to win the US Open after dropping the first two sets of the final.
Thiem tied up the fifth set 5-5 with an incredible shot, too, and then broke Zverev to take a 6-5 lead.
Zverev faltered on serve at 3-4 in a high-quality fourth set allowing Thiem to take the contest to a decider.
In a rollercoaster decider inside a quiet Arthur Ashe Stadium, Thiem - playing his fourth major final - eventually closed out a 2-6, 4-6, 6-4, 6-3, 7-6 (8-6) victory.
It took him a while to get going - in fact, nearly too long - but Dominic Thiem picked up his first Grand Slam title on Sunday night.
He fell as the first first-time Grand Slam champion since Marin Cilic at the 2014 U.S. Open, after six long, long years of unbroken rule from the royals.
Thiem earned his first Grand Slam title Sunday with a 2-6, 4-6, 6-4, 6-3, 7-6 (6) comeback victory against Alexander Zverev.
Theim avoided another break point from Zeverev to start off the second set, but he couldn't keep Zverev at bay for long and fell into a 5-1 hole nearly instantly.
Zverev roared into a two-set lead with the Austrian not able to establish himself at all, but that was just the beginning of the drama.
The German was helped by some sloppy serving from Thiem, who hit three double faults as he was broken twice, in games three and seven. He took a medical timeout before it was his turn to serve for the championship. Zverev smashed 15 aces compared to Thiem's two.
Thiem was down early and it was looking like Zverev was going to get the best of the Austrian.
He won the title and the winner's cheque of $3 million on his third after Zverev hit it wide.
This year's field at the Billie Jean King US National Tennis Center in NY was depleted by the absence of Swiss legend Federer and defending champion Nadal.