Thiem earned his first grand slam title with a 2-6 4-6 6-4 6-3 7-6 (8-6) comeback victory against Alexander Zverev.
The US Open had never been decided by a fifth-set tiebreaker before.
Pancho Gonzalez made a similar turnaround against Ted Schroeder in 1949 to win the event, then known as the US Championships.
The 27-year-old Thiem entered the final with a 0-3 career record in major title matches.
This was fifth-seed Zverev's debut in a grand slam final.
Thiem, the number two seed and world number three, became the first Austrian to claim a singles title at Flushing Meadows, albeit in unique circumstances as no fans were present at the hardcourt major due to the COVID-19 pandemic.
