The fire broke out at an apartment building in Hamilton Heights just after 4 a.m. Wednesday.
The residents, ages 22 and 23, were critically injured after they jumped from the windows of the West 147th Street building.
One resident said he awoke to the sound of a body hitting the ground outside his bedroom window.
Witnesses say a third person climbed out a second-floor window and shimmied across a ledge on the facade of the building to safety.
Seven firefighters were also being treated after battling the second-alarm blaze.
The cause of the fire is under investigation. Residents say a fire broke out in the same building about a month ago. That fire was deemed suspicious. The building has reportedly been in foreclosure twice.