Large crowds squared off with the police in Union Square, Columbus Circle, lower Manhattan and in several neighborhoods in Brooklyn, including the area around Barclays Center.
As of 11 p.m., there were still an estimated 1,500 protesters in downtown Brooklyn. A number of police cars were set on fire and demonstrators vandalized stores and banks.
Mayor Bill de Blasio in a late-night news conference condemned the "small number" of agitators who are determined to be violent. He said the NYPD was working to get these "violent protesters" off the street, and he noted that these demonstrations are not like traditional protests in NYC, suggesting that "out of towners" might be in the mix.
Demonstrations during daylight hours were mostly peaceful, but as evening fell protesters hurled objects at officers, set numerous fires, torched and smashed police vehicles and blocked roads with garbage and wreckage.
Dangerous confrontations flared repeatedly. Video showed two police cruisers lurching into a crowd of demonstrators on a Brooklyn street, knocking several to the ground, after people attacked it with thrown objects, including something on fire. It was unclear whether anyone was hurt.
Asked about the video, de Blasio said the protesters should not have surrounded the car, and that this is not the usual behavior he's seen at protests over the years, suggesting that a "different element" is at play in these protests.
"If the police officers are in that situation they have to get out of that situation. I wish the officers had not done that, but I also understood they did not start the situation, the situation was started by protesters converging on a police vehicle, attacking that vehicle. It is unacceptable."
In numerous flare-ups around the city, officers sprayed crowds with chemicals. Protesters smashed the windows on police vehicles, sprayed them with paint and set a patrol car on fire.
Videos showed protesters dancing on top of a smashed police van, its lights still flashing.
The protests, among many around the country over the killing of George Floyd by a police officer in Minnesota, came a day after several thousand people faced off with a force of officers on the streets around a Brooklyn sports arena.
The scope of the protests was captured by an alert from Notify NYC: "Due to ongoing protest activity, expect traffic delays, road closures, mass transit disruptions, cancellations, delays and a heavy presence of emergency personnel in the area of Columbus Circle, Union Square in Manhattan, and the Barclays Center in Brooklyn. Consider alternate routes and allow for additional travel time."
Earlier, rocks were thrown at police, and fires were set in midtown at West 45th Street and Seventh Avenue. There have been minor injuries to a number of officers.
"We had some people try to take over the FDR Drive," NYPD Chief of Department Terry Monahan told ABC News. "Some groups took over the West Side Highway."
The NYPD was hoping to prevent "mayhem" that was seen in parts of Brooklyn, but vast, violent protests materialized again.
"If a protest is peaceful and not causing damage, not causing mayhem we want to encourage people to protest," Monahan said. "As soon as there's some sort of damage or mayhem we're going to take action."
Earlier, video surfaced on social media showing a woman being violently shoved to the ground by an NYPD officer near the Barclays Center. In addition, two sisters from the Catskills were arrested for allegedly throwing a Molotov cocktail at an NYPD van occupied by four officers during Friday night's violent protests in Brooklyn. No one was burned.
Police are still counting their injured from Friday - one officer had his teeth knocked out.
Monahan insisted the NYPD was "surgical" in its use of force Friday night despite complaints from Mayor Bill de Blasio about "elected officials at this protest some of whom were pepper sprayed."
What happened outside Barclays Center was described by Monahan as "an organized attempt to attack police" with bottles, bricks, Molotov cocktails and other debris and he blamed "a lot of outsiders," instigators who "were not people from our communities."
Monahan urged protesters peacefully expressing their anger over Floyd's death to move away if they see demonstrators around them getting violent
"If you see people starting to act up, starting to deliberately attack police or destroy property, don't let them use you as camouflage," Monahan said. "Do not get sucked in."
The mayor and police commissioner are walking a fine line - defending the right of protesters and angry over the killing of George Floyd in Minneapolis. Yet at the same time they're calling protesters determined to cause trouble and determined to hurt police.
"And that's why I say I figuratively - I stand with the protesters, but violence is not the answer. It is never the answer," Governor Andrew Cuomo said on Saturday.
The Associated Press contributed to this report.