The 19 time Grand Slam Champion was beaten in four sets by Juan Martin del Potro.
The Argentine will now face Rafael Nadal in the semi-finals.
It is women’s semi-final day in New York and there is and all-American line-up for the first time since 1981.
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Two-time champion Venus Williams will play Madison Keys.
That will be followed by the meeting of Sloane Stephens and CoCo Vandeweghe.
Ireland’s Simon Carr aims to reach his first ever junior Grand Slam quarter-final later.
The son of former Tipp footballer Tommy Carr faces Russian Timofey Skatof in the last-16 of the U-S boys Open in New York.
