The incident began at about 1:50 a.m. Sunday when the intruder broke into a home in the 12300 block of 11th Avenue NE, where the victim and his roommate live and operate a marijuana grow operation.
The homeowner confronted the intruder, who then opened fire, shooting the homeowner in the chest, said Seattle police spokeswoman Renee Witt.
The suspect then fled the house.
Officers who responded to the scene brought in a K-9 police dog and conducted a search, but the suspect could not be found.
The victim was taken to the hospital with life-threatening injuries. He later died, family members told KOMO News.
The shooting shook up residents of the usually quiet neighborhood, who said the homeowner didn't deserve to die.
"A life is a life regardless of who it is and where it is - it's a life. And you can't replace a life," said one neighbor.
The suspect is described as an Asian male, about 20 to 30 years old, of medium height, with a slim build and short black hair. He was wearing a dark jacket.
It wasn't immediately clear whether the break-in was drug-related or whether the marijuana grow was legal or illegal.
While officers were at the scene of the home invasion, a second homeowner called in a burglary at a residence near NE 125th Street and 12th Avenue NE. Officers quickly responded to that location and checked the house, but the suspect was gone. It is unknown if this was the same suspect.
Witt said this remains an open and active investigation.