Federer, the five-time champion and looking to end his 10-year wait to add to his total in New York, was beaten by Australia’s world number 55 John Millman 3-6, 7-5, 7-6 (9/7), 7-6 (7/3).
It was 20-time major winner Federer’s first loss against a player outside the top 50 in 41 meetings at the US Open.
He finished with 77 unforced errors and 10 double faults.
It was the world number two’s earliest defeat at the tournament since a fourth round loss to Tommy Robredo in 2013.
Here is how Twitter reacted to his loss:
Limited-time offer: Big stories, small price. Keep independent media alive. Become a Scroll member today!
Our journalism is for everyone. But you can get special privileges by buying an annual Scroll Membership. Sign up today!