The four victims had been pulled from the burning upstate New York home by firefighters and medics but died later.
The blaze swept through the two-story home, on a tidy block in the riverside city of Elmira, south of New York's Finger Lakes near the Pennsylvania border, on Friday night. Fire officials said the building was engulfed in flames when they arrived.
Police didn't immediately release the names and ages of the victims but confirmed on Saturday that children were among them.
Neighbor Glen Bolt told the Elmira Star-Gazette that he ran across the street when he saw flames pouring out of the home's windows and front door. He said the children in the home ranged in age from around 5 to 15.
"Me and the neighbor there busted the windows out, hoping the kids would come through that window," said Bolt, 72. "But by that time the smoke had already got them."
Firefighters had the blaze under control fairly quickly, officials said. The victims were found on the second floor in the home, said Mark Cicora, the deputy director of operations for the Chemung County Office of Fire and Emergency Management.
The cause and circumstances of the fire were under investigation.
Information from: Star-Gazette