One of the victims was shot in the leg and the other was injured in a freeway collision with the shooter's car, the agency says.
The incident happened near the Oak Hill Road ramp around 9:30 a.m.
Investigators say it appears there was some kind of incident on the road involving the drivers of a white Ford F-350 pickup and a black Volvo XC70. They exchanged words and honked while driving.
The Volvo driver then pulled out a gun and fired at the truck. At least two bullet holes were later visible on the driver's side of the pickup after the incident. Police say the Ford driver was shot in the leg.
The Volvo then collided with a third vehicle a white Toyota Tundra pickup and the Volvo then fled the scene.
"As the vehicles continued southbound they interacted with each other, causing both of those vehicles to collide with each other, which resulted in the black Volvo colliding with another uninvolved vehicle, which was a white Toyota Tundra," said CHP Capt. Lance Berns.
Southbound lanes of the 15 near the Cajon Pass were shut down for hours, only reopening around 2 p.m., creating a massive traffic backup.
The drivers of the two trucks were hospitalized with non-life-threatening injuries. Authorities are still searching for the black Volvo, which is believed to have damage to the front and rear bumpers.
The CHP offered advice for drivers who may find themselves upset at the actions of other motorists.
"Drive to your destination, follow the speed laws and don't engage with other vehicles," Berns said. "If an incident occurs where there is an unsafe lane change, do not escalate it into something that is more serious."