The fire broke out around 6:00 a.m. along the 2100 block of Silverside Road in Brandywine Hundred.
State troopers arrived first and rescued a man and woman from the home.
Both suffered smoke inhalation and were treated and released from Chistianacare Wilmington Hospital.
Investigators say the flames originated in a second floor bedroom and was caused by discarded smoking materials.
Residents were not able to return to the residence and are staying with family.