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 6-3 7-5 triumph on Saturday.
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.
The fearless 19-year-old is also the first Canadian to win a singles grand slam and first teenager to hoist the US Open trophy since Maria Sharapova in 2006.
Andreescu won the hearts of Auckland tennis fans with her giantkiller run in the ASB Open at the start of the year before losing the final and with her and Williams confirmed to return to Auckland in 2020, a US Open final rematch is on the cards.
Andreescu started the season ranked 178th in the world. She failed to even qualify for the US Open last year.
It was a second consecutive defeat in the US Open women's singles finals for Williams who in 2018 lost in dramatic circumstances to Japan's Naomi Osaka.
"It's so hard to explain in words but I'm just beyond grateful and truly blessed," Andreescu said after improving her record over top-10 rivals in 2019 to a remarkable eight from eight with her third title of the season.
"I've worked really hard for this moment. This year has been a dream come true and now, to play Serena on this stage, a true legend of this sport, is amazing."
Not even born when Williams won the first of six titles in New York in 1999, Andreescu defied the doubters with an extraordinary baseline barrage as Williams once again crumbled under pressure trying to match Margaret Court's 24 singles slams.
It was the fourth consecutive grand slam final defeat for the American since returning from maternity leave after the birth of her daughter Olympia in September 2017.
But this one will likely hurt most with Williams injury free and finally back to full fitness, adamant pre-match she'd never been better prepared to return to the grand slam winners' circle.
Alas, after also falling to Naomi Osaka in last year's final and to Angelique Kerber and Simona Halep in the past two Wimbledon deciders, time may be running out for Williams - who turns 38 this month - to catch Court.
But she was gracious in defeat.