The incident sparked pandemonium in one of the city's busiest tourist and leisure centers, as bloodied victims were hauled away on stretchers and the vehicle lay upended and steaming on a sidewalk.
The chaotic scene raised fears of terrorism following a series of recent attacks in Europe in which speeding vehicles were used against pedestrians. But law enforcement officials said that did not appear to be a factor in this case.
"Based on the information we have at this moment, there is no indication that this was an act of terrorism," New York Mayor Bill de Blasio told reporters.
"That being said, we are reinforcing key locations around the city with our anti-terror units of the NYPD," he said. "It's a tough day for New York City, but as usual the people of New York City will stand firm, will be resilient."
The driver, identified by police as 26-year-old Richard Rojas, was tackled by a traffic officer and bystanders as he tried to flee the scene.
Rojas, a resident of the Bronx, tested negative for alcohol on an initial examination, two unidentified law enforcement officers told the Associated Press. He told officers he was hearing voices and expected to die, they said.
Authorities said the mayhem began shortly before noon, when a car driving south on 7th Avenue made a U-turn at 42nd Street, then drove onto the sidewalk and sped north against traffic for three blocks before flipping on a row of short security posts at the corner of 45th Street and Broadway.
Along the way, 23 pedestrians were struck, with four of them critically injured, police said.
Emergency vehicles with sirens blaring rushed to the corner where the maroon Honda Accord lay tilted against a stanchion, its right wheels in the air.
The pedestrian who was killed was identified as Alyssa Elsman, an 18-year-old tourist from Michigan.
She graduated last year from Portage Central High School, where the principal remembered her as a smart and engaging student who was an exceptional baker and very active in the school's culinary program.
"She would make the most wonderful muffins, and the students would sell them before school to help raise money for the program," Principal Eric Alburtus said in a statement.
Elsman's 13-year-old sister, Ava, was injured in the incident and transported to a hospital.
Angela Opara, 40, was standing across the street from the sisters with a friend who was distributing fliers for a tour company.
"He was coming so fast," she said of the driver. "He was coming right up on the sidewalk, taking innocent people, bringing them down."
She thought perhaps the driver was drunk or the vehicle's brakes had failed. But her companion, Frederick Nyamekeh, was convinced the driver had acted deliberately.
"If it was not for that last pillar that he hit, he would have gone on to hit more people in the pedestrian plaza," said Nyamckeh, 42.
More than 200 stainless steel posts were installed last year to protect the sidewalks around Times Square in the event of a vehicular terrorist attack or accident, said Robert Reiter, chief security consultant for Calpipe Security Bollards, the Rancho Dominguez-based company that manufactured the posts.
Isabel Chang, 40, and a colleague were waiting for an Uber ride when she heard screams from a few blocks away. Then she saw a car plowing down the opposite side of the street.
"He wasn't swerving, and it felt intentional," Chang said. "Then I saw people who didn't move away fast enough get hit and fly off to the side."
By the time the car stopped, Chang said, she saw three bodies lying on the street. As the driver got out of the vehicle, he appeared to be limping.
"I saw people grab his shirt to stop him and when he started coming toward our direction, that's when my colleague said we need to go," she said.
Brad Hoylman, a New York state senator, arrived at Times Square moments after the crash. He said he saw a "very large and impressive" man who worked at Planet Hollywood rush out of the restaurant and help a traffic officer tackle the driver, who was trying to flee.
"It was an absolutely sickening scene," he said. "There was this demolished car, and wreckage strewn all over the street."
Evan Stemmer, 25, who was visiting from Detroit, said he was returning to his hotel with a friend when they heard the sirens and saw the arrest.
"We could see that there was someone being pulled and a struggle," he said. "And on each block, there was somebody lying on the sidewalk."
Police said Rojas is a Navy veteran and has two prior arrests, in 2008 and 2015, for driving under the influence. He was also arrested this month for an unspecified drug-related offense, they said.
Police cordoned off the entrance to the building on Walton Avenue in the Bronx where Rojas lived in a fifth-floor apartment with his mother.
On the sidewalk outside, Harrison Ramos, 30, described himself as a friend of Rojas, having known him since their high school years.
Ramos said the suspect wanted to work in real estate and had printed up business cards, though he didn't know whether Rojas was currently employed. He said Rojas was close to his family and liked to play video games.
"When he came back from serving [in the Navy], that was when he started drinking a lot," Ramos said.
"He didn't come back normal," he said. "So, yes, he was intoxicated; he kept dreaming crazy dreams."
Recently, he said, Rojas had been posting "crazy things" on his Instagram account, which was no longer active Thursday.
The last time he saw his friend was about a week ago on a street in the neighborhood. "He looked a little lost in this world."
Times staff writer Demick and special correspondent Haller reported from New York and staff writer Zavis from Los Angeles. Staff writers Kurtis Lee and Melissa Etehad in Los Angeles contributed to this report.
9:25 p.m: The article was updated with additional background on recent attacks in which vehicles were used against pedestrians.
5:10 p.m.: The article was updated with more details about the woman killed and her sister.
3:10 p.m.: The article was updated with the identity of the pedestrian who was killed.
2:40 p.m.: The article was updated with comments from an acquaintance of the driver.
12:50 p.m.: The article was updated with additional accounts from witnesses.
11:07 a.m. The article was updated with information about the pedestrian who was killed and reports of an arrest earlier this month of the driver on a drug-related charge.
10:40 a.m.: The article was updated with additional details of the incident, the identity of the driver, and an increase in the number of injuries.
10:10 a.m.: The article was updated with news of additional injuries.
9:45 a.m.: This article was updated with news of a fatality.
9:30 a.m.: This article was updated with reports of at least 13 people injured.