The Houston Chronicle reported it was the worst toll in the fire department's history.
"Today is going to go down as the worst day in the history of the Houston Fire Department," Mayor Annise Parker said. "We ask for every Houstonian to offer their prayers for the families of these fallen firefighters."
Fire Chief Terry Garrison said the four were fatally injured when the motel's roof collapsed while they were searching for possible civilians trapped inside.
"They were risking their lives to save the community," he said. "Unfortunately, the building had much more fire than we originally thought. The structure collapsed."
KHOU-TV, Houston, reported three firefighters' bodies were found in the rubble of the Southwest Inn motel and the fourth firefighter died at a hospital.
The fatalities were identified as Capt. EMT Matthew Renaud, 35, of Station, 51; firefighter EMT Robert Garner, 29, of Station 68; probationary firefighter Anne Sullivan, 24, of Station 68; and engineer operator EMT Robert Bebee, 41, of Station 51.
The TV station said Sullivan just graduated from the academy last month.
"Houston firefighters mourn the loss of our three brothers and our sister and will forever honor their sacrifices," Jeff Caynon, president of the Houston Professional Firefighters Association, said. "This tragedy underscores the inherent dangers of our profession. Please keep Houston firefighters in your thoughts and prayers."
The fire broke out shortly before noon and took more than 3 hours to bring under control. No cause for the blaze was provided.