Another 11 were injured after the suspect opened fire at a banquet hall in Stockton, California.
Local authorities confirmed reports of the shooting were received just after 6pm.
The victims include both adults and children as they were all rushed to hospital, authorities said.
Those killed in the mass shooting were ages eight, nine, 14 and 21, police said.
The injured include a nine-year-old, 12 and 15-year-old young adults under the age of 22, authorities added.
They revealed that the gunman fled the scene and remains at large.
The San Joaquin County Sheriff’s office said: “This is a very active and ongoing investigation, and information remains limited.
“Early indications suggest this may be a targeted incident, and investigators are exploring all possibilities.”
Police spokesperson Heather Brent described the incident as “unfathomable”.
She added: “Our number one priority is identifying the suspect in this incident.”
California police have pleaded with the public for help identifying the shooter.
Stockton’s vice mayor Jason Lee said the shooting unfolded at a child’s birthday party.
He said: “My heart is heavy in a way that’s hard to put into words. I am devastated and angry to learn about the mass shooting at a child’s birthday party.
“A birthday party should never be a place where families fear for their lives.
“Violence touched my life as a young person, and seeing our own children, parents, and neighbours go through this shakes me deeply.
“Stockton is my home. These are our families. This is our community.
“I’m sending my thoughts, prayers, and love to the families who are hurting, to the children who witnessed this trauma, and to everyone across our city who feels this pain.”
California Governor Gavin Newsom has been briefed on the shooting, according to reports.