At least four of the injured in the seven-alarm fire were in critical condition, a fire department spokesman said.
Some people may be trapped in the blaze, a law enforcement source said.
Several law enforcement sources told CNN that there is no indication that this was related to terrorism — all said it appeared to be a gas explosion.
The first two floors of a red-brick building at the scene appear to have crumbled, images from the scene showed.
Luca Babini, 25, said he was in his office less than a block away at the time of the blast.
“Everything, my shelf in my office and my computer screen fell down,” he said. “They say it was a gas leak.”
Babini said a man immediately climbed a fire escape in an attempt to rescue people trapped in the collapsed building.
“I saw a lot of people lined up at the streets trying to help,” he said.
Towering flames and plumes of black smoke at one point rose from the building, which includes both apartments and businesses. Emergency personnel could be seen taking the injured away on stretchers.
At least 250 firefighters were on the scene.
The collapsed first floor houses a Japanese restaurant; the building next door, with a shop specializing in French fries on the street level, was ablaze and, in later images, appeared to have completely collapsed.
The explosion comes just over a year after two buildings in Harlem collapsed after a gas leak last March, killing eight people and injuring dozens. The buildings were served by a 127-year-old gas main.
After the 2014 incident, experts warned that many U.S. utilities were struggling to maintain or replace antiquated, hard-to-reach and leaky gas mains in older urban areas. The most vulnerable mains are made of cast iron or steel.
A day before the Harlem explosion, the New York-based Center for an Urban Future said in a report that New York’s aging infrastructure “could wreak havoc on the city’s economy and quality of life.” An estimated $47.3 billion would have to be devoted for repairs to maintain safety.
The average age of New York City’s 6,300 miles of gas mains is 56 years old, wrote the report’s author, Adam Forman.