It happened around 9 a.m. on Park Avenue on 116th Street, the FDNY said. One of the buildings that collapsed had a piano repair shop with apartments above. The second building housed a church.
Officials believe both buildings were 5-stories. Evacuations are under way in the area.
WCBS reports at least two people, both female, were killed in the explosion. The FDNY says 16 injuries have also been reported, four serious and 12 minor. Harlem Hospital says it received one patient with serious trauma.
Video from the scene shows huge flames and billowing smoke as hundreds of firefighters battle the blaze, which was upgraded to five-alarms. Debris and rubble could be seen scattered all over the area.
Witnesses reported hearing a loud explosion.
"I was home and then next thing you know I'm laying down and I hear this big explosion. I came out, looked up and a building was just gone," eyewitness Mack Mayor told CBS 2. "It's just like a war zone out here."
"The smoke started to rise. It looked like something fell because it wasn't like a fire. It just looked like debris smoke, similar to 9/11," said witness Samuel Paul, who was on the 15th floor of a building on 125th Street.
Federal officials tell CBS News early indications are that the building explosion is the result of a gas leak. Con Edison confirms there were crews en route to the area at the time of the explosion after the company received a call Wednesday morning from a woman who smelled gas.
"Last night when we came out of church, at the corner outside in the street there was a smell of gas," she said. "It would come and go, so I thought it was from the corner store there so I went to the owners and told them and they said they would look into it and then we went home."
It's unclear if anyone was inside the buildings at the time of the explosion, but Vargas-Rosa said four of her tenants are unaccounted for
"One of them was off from work so most likely she was in the building," Vargas-Rosa said. "We have a mother who has a sick son, so unless they were at an appointment in the hospital, they may have been in the explosion and then we have a young man and his wife who go to school late so they may have been sleeping and we can't reach them."
Mayor Bill de Blasio is en route to the scene. The NYPD has ruled out terrorism as a cause of the explosion, but the bomb squad and the FBI are both on the scene.
Metro-North said the explosion happened adjacent to their tracks. Service in and out of Grand Central Terminal is suspended until further notice.
The bomb squad is also responding as a precaution.