Williams, who indicated her intention to retire earlier this month but never confirmed the US Open as her final tournament, beat Montenegro's Danka Kovinic 6-3 6-3 in front of a packed Arthur Ashe Stadium.
"I've been pretty vague about it, right," Williams said. "I'm going to stay vague because you never know."
Former world No.1 Halep suffered a shock first-round exit to Ukrainian qualifier Daria Snigur, who won 6-2 0-6 6-4 on her Grand Slam main draw debut, while last year's finalist Leylah Fernandez saw off Oceane Dodin of France 6-3 6-4.
An already depleted men's draw opened up even further after Tsitsipas was knocked out by Colombian qualifier Daniel Galan, who clinched the 6-0 6-1 3-6 7-5 win on his ninth match point.
Top American seed Taylor Fritz was ousted by compatriot and qualifier Brandon Holt, the son of former two-time US Open champion Tracy Austin, who marked his Tour level debut with an upset 6-7(3) 7-6(1) 6-3 6-4 win.
Russia's Daniil Medvedev, barred from competing at Wimbledon due to his country's invasion of Ukraine, returned to the Grand Slam stage in New York and began his US Open title defence by crushing American Stefan Kozlov 6-2 6-4 6-0.
KYRGIOS BEATS KOKKINAKIS
Wimbledon finalist Nick Kyrgios triumphed over doubles partner Thanasi Kokkinakis 6-3 6-4 7-6(4) in an all-Australian affair at Arthur Ashe Stadium, powering to victory in two hours.
"When we both saw the draw, it was a nightmare," said Kyrgios, who won the Australian Open doubles title with Kokkinakis earlier this year. "We're going to play each other, hopefully, never again."
KONTAVEIT THROUGH IN 66 MINUTES
Second seed Anett Kontaveit of Estonia cruised into the second round with a 6-3 6-0 win over Jaqueline Cristian in 66 minutes, firing 20 winners past the Romanian while dropping only four points on her first serve.
FORMER CHAMPION THIEM KNOCKED OUT
Austrian Dominic Thiem was knocked out in the first round after 12th seed Pablo Carreno Busta beat the 2020 champion 7-5 6-1 5-7 6-3.
JABEUR, KEYS ADVANCE
Wimbledon finalist and fifth seed Ons Jabeur beat American Madison Brengle 7-5 6-2 to move into the second round.
Brengle's compatriot Madison Keys, however, gave the home crowd reason to cheer after she beat Ukrainian Dayana Yastremska 7-6(3) 6-3.
GAUFF WINS FOR FIRST TIME ON ASHE
American Coco Gauff won her first match at Arthur Ashe Stadium with a 6-2 6-3 victory over France's Leolia Jeanjean.
VAN RIJTHOVEN SAVES SEVEN MATCH POINTS TO ADVANCE
Tim van Rijthoven saved seven match points in the third set against China's Zhang Zhizhen to seal an improbable comeback victory, winning 3-6 6-7(4) 7-6(9) 6-1 6-4.
BERRETTINI THROUGH TO SECOND ROUND
Matteo Berrettini beat Nicolas Jarry 6-2 6-3 6-3, becoming the Italian player with the most main draw wins at Flushing Meadows with 13 victories.
WU CHINA'S FIRST WINNER AT GRAND SLAM SINCE 1959
Wu Yibing became the first man from China in 63 years to win a Grand Slam singles match when he beat Nikoloz Basilashvili 6-3 6-4 6-0.
AMERICAN PAUL WINS IN FIRST FIVE-SETTER OF US OPEN
American Tommy Paul came from behind twice to beat Spain's Bernabe Zapata Miralles 4-6 6-3 2-6 6-0 7-5 in what was the first five-setter of the tournament and his first career win at his home Grand Slam.
MURRAY CRUISES THROUGH TO SECOND ROUND
Former champion Andy Murray began his campaign with a 7-5 6-3 6-3 win over Argentine 24th seed Francisco Cerundolo, who made several unforced errors.
"Very tricky conditions, very humid and hot but I was really happy with the way I got through that one," Murray said following his win at Louis Armstrong Stadium.
SAKKARI DOWNS MARIA
Third seed Maria Sakkari overcame a wobble to beat Tatjana Maria 6-4 3-6 6-0 and gain revenge against the German who upset her en route to the Wimbledon semi-finals this year.
Also reaching the second round were Caroline Garcia who beat Kamilla Rakhimova 6-2 6-4 and Veronika Kudermetova after her 7-5 6-3 victory over Donna Vekic.
