Li, seeded sixth, lost 6-2, 7-5 on Tuesday. The second round at Flushing Meadows will be without all three of this year's major champions. Australian Open winner Kim Clijsters withdrew because of injury, while Wimbledon champ Petra Kvitova lost Monday. It's the first time that's happened since 1971.
Since Roland Garros, Li had not won consecutive matches until last week, when she reached the semifinals at New Haven.
The 19-year-old Halep beat a top-10 player for the first time in four tries. The Romanian was playing in her second U.S. Open match.
The match ended on Li's 54th unforced error.
Top-seeded Caroline Wozniacki, still seeking her first major title, cruised into the second round Tuesday.
Wozniacki beat Nuria Llagostera Vives of Spain 6-3, 6-1 in 1 hour, 20 minutes. She won last weekend at New Haven to regain some momentum heading into the Open.
It was a drama-free afternoon in Arthur Ashe Stadium that left the most interesting stuff for the post-match interview.
How were things going with Rory McIlroy, golf's reigning U.S. Open champion whom she started dating this summer?
"You know, he has something I'm looking for and I have something he's looking for," she said. "He wants to be No. 1. So it's good to have something on each other."
Does the No. 1 ranking, when it's not accompanied by a major title, feel like a burden or an honor?
"I'm trying to stay up there as long as possible, and it doesn't really matter what people are saying," she said. "No one can ever take that away from me."
And why not end the suspense and tell us who that new coach of yours is?
"Yeah, well, I have to respect him, as well," she said. "So if he wants to be in the background and not have his name out, I have to respect that."
Though she's refusing to name names, Wozniacki is clearly looking for another gear and a few more weapons as she tries to add to a resume that includes 46 of the last 47 weeks at No. 1 but no major championships and only one trip to a Grand Slam final -- two years ago at the U.S. Open, when she lost to Kim Clijsters.
She had what some viewed as a rough summer, losing her first match at both Toronto and Cincinnati—considered key leadups to the year's last Grand Slam. But last week, she won for the fourth straight year at New Haven, and suddenly, the critics seem more like alarmists.
"I know that I'm back on track," she said. "I know that everyone has to write their stories, but I think we should move on. Ask me about something else, something more interesting."
There wasn't much interesting about this match, except maybe for the observation that Wozniacki didn't need to bring out any new weapons to defeat Llagostera Vives, the diminutive counterpuncher ranked 125th and playing her first singles match on the U.S. Open main show court.
This was typical Wozniacki—steady groundstrokes and long points, made longer on a surface that players say has been playing slower this year.
A number of the ex-players who now work as analysts on TV say Wozniacki's kind of game isn't suited to winning Grand Slams, especially not the kind of grind that the U.S. Open can be.
Wozniacki isn't listening.
"They can say what they want," she said. "I'm the type of player I am. I've won a lot of tournaments. I'm No. 1 in the world, and of course I can still improve. There are a lot of things to my game I can still improve, but everyone can."
Fourth-seeded Victoria Azarenka also advanced easily to the second round, beating 60th-ranked Johanna Larsson of Sweden 6-1, 6-3 in Arthur Ashe Stadium.
Azarenka broke Larsson's serve to convert her first match point and win in just 70 minutes.
The fifth-ranked player from Belarus had pulled out of the U.S. Open warmup in Cincinnati with a right hand strain. This is the only major tournament where she has never reached the quarterfinals.
Azarenka could potentially face Serena Williams in the third round this time. She had to retire in the second round last year, collapsing because of a concussion suffered in a fall before the match.
Azarenka won 77 percent of points on her second serve Tuesday, even better than the 72 percent on her first serve.
Seventh-seeded Francesca Schiavone overcame a spate of double-faults to beat qualifier Galina Voskoboeva in three sets.
The Italian had four double-faults in trying to serve out the match, but promptly broke Voskoboeva's serve to clinch a 6-3, 1-6, 6-4 victory.
Schiavone threw her cap in frustration after the match, then smiled as she waved to the crowd.
Schiavone won the 2010 French Open before losing in the final this year. She had 16 double-faults Tuesday and got just half of her first serves in.
Voskoboeva, the 87th-ranked player from Kazakhstan, had 32 winners but 46 unforced errors.
Former French Open champion Ana Ivanovic won her first-round match, defeating Ksenia Pervak of Russia 6-4, 6-2.
Ivanovic is still mourning the death of her grandfather, Milovan, who passed away over the weekend. She was able to set it aside for most of Tuesday's match, but near the end, she said emotions got the best of her.
"I had quite a tough weekend," she said. "When I was serving for the match, I kept thinking, 'I'm doing it for him.'"
The 16th-seeded Ivanovic, moving her way back up the rankings after falling into the 60s last year, took a 5-2 lead in the second set but laid down on the sideline and required a visit from the trainer during the changeover.
She returned to the court and broke Pervak's serve to close out the match and avoid going out in the first round of a grand slam for the third time this year.
Part of her resurgence could have to do with a reconciliation with golfer Adam Scott, who was in the stands for the opening-round match. At the beginning of the year, Ivanovic told the (Sydney) Sunday Telegraph that her on-court performance had suffered in the aftermath of a breakup with Scott.
Asked on Tuesday if Scott's presence in the stands meant they were back together, she said, "It was really nice to see him there. Now we're just happy, and that's all that matters."
Every bit as much on her mind, however, was her grandfather.
Ivanovic choked back tears while describing a very close relationship with Milovan Ivanovic but said she had no regrets about playing so soon after his death; she believes he would want her to be out on the court competing.
"In the last couple of years, I've had to deal with many different things, many different issues out there," she said. "I've just tried to put it aside and try to focus on hitting the ball. There are moments where things creep in a little more. But it's important to be in the moment and think more tactically and take your mind off that."