It happened shortly after noon Sunday at a two-story home on the 300 block of Main Street in Little Creek, right across the street from the Little Creek Volunteer Fire Company.
According to Fire Chief Michael Scott Bundek, firefighters responded within one minute of getting the call.
They received reports of people trapped inside the home.
Crews located the 9-year-old and two other victims.
Chief Bundek said one person jumped out a second-floor window before firefighters arrived to escape the flames.
The Delaware Office of the State Fire Marshal said five victims were taken to Bayhealth Hospital - Kent Campus in Dover for smoke inhalation and burns.
The 9-year-old girl and a 42-year-old woman died at the hospital, the Fire Marshal said.
Three other victims remain in critical condition.
The Fire Marshal said two of those victims were expected to be transferred to the Crozer-Chester Medical Center in Upland, Pennsylvania.
Authorities have not identified the victims.
The cause of the fire remains under investigation.
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