It happened at 43 4th Street around 11 a.m.
The home had undergone some recent renovation and it is believed that it was a gas explosion.
People report hearing and feeling the blast from miles away.
21 people were taken to the hospital, all non-life-threatening and non-traumatic injuries.
Resident Brian Lawrence said, "Stuff was flying down, 2 by 4s, roofing, everything was coming down."
Fourth Street blew up and according to resident Reginald Patterson this is what it was like, "If you ever heard any bombs go off, that's exactly what it reminds you of, a bomb."
The blast sent debris into trees, cars and living rooms.
"Came outside there was nothing left across the street. Just a big flame," one neighbor said.
A police dog searched the demolished home for victims.
It had been vacant. A development company recently renovated it and put it on the market.
And while 21 neighbors went to the hospital, every single injury was minor.
Arson investigators spent the afternoon treating Fourth Street as a crime scene, trying to pinpoint the cause of the gas leak and the spark that ignited it.
"We'll start excavating, de-layering the debris, looking for some obvious things like appliances that should be there that aren't there," said Detective Sergeant Edward Fitzgerald from the Suffolk County Police Department.
Stuart Cohen and his wife Cindy are counting their blessings.
They live right across the street and had been sitting in their living room minutes before the blast.
It left cracks in their wall and turned their quiet holiday upside down.
"I'm just happy my wife's OK, my father's OK, my mother, my dogs; all this can be replaced," Stuart Cohen said.