Ranked 178th in the world at the start of year, Andreescu overcame a dramatic second-set collapse to deny Williams a record-equalling 24th grand slam singles crown with a stirring triumph to claimed Canada's first grand slam singles title.
Title success on her main-draw debut at Flushing Meadows marked the equal-fastest journey to grand slam glory in tennis history, matching Monica Seles' feat in winning the 1990 French Open in only her fourth major.
It's Williams' fourth straight loss in a slam decider and her wait for a record-tying 24th major continues.
Andreescu was made to wait, as Williams erased a 1-5 deficit in the second set, but the teenager held her nerve to close out the biggest match of her career.