It happened around 11:00 a.m. Friday on the 300 block of East 24th Street.
Officials say the flames came from the 2nd floor of the home.
Two adults and two children lived there but no one was home at the time of the blaze.
Fire crews brought the flames under control by 11:40 and no one was injured.
The family's home suffered heavy fire damage to the second floor and a substantial amount of smoke and water damage throughout. A neighboring home also suffered smoke damage.
The Wilmington Fire Marshal's Office is investigating the cause of the blaze.