Authorities said the 3-year-old boy somehow got his hands on an unsecured handgun Monday morning. The girl was taken to a local hospital by firefighters where she died an hour later.
The identities of the siblings were not released.
According to officials, homicide detectives are continuing to investigate the circumstances of the shooting.
The sheriff's department said the district attorney's office has been notified.
Per California law, firearms at home are required to be stored in locked containers or disabled by security devices.
Fallbrook is located about 56 miles north of San Diego.
According to the Everytown for Gun Safety advocacy group, there have been more than 200 unintentional shootings by children in the U.S. so far this year, including six others in California.
The Associated Press contributed to this report.