Thiem won 2-6, 4-6, 6-4, 6-3, 7-6 (6) in a match that lasted over four hours. 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.
The mental struggle to make a major breakthrough was apparent in the tense final set. Zverev broke for a 5-3 lead and served for the title, but Thiem broke right back and won the next three games, giving him a chance to serve for the match.
Zverev then broke him to force the tiebreaker, but then double-faulted twice in it.
Thiem had lost in his first three major finals.
The Associated Press contributed to this report.