The crash was reported just after 4 p.m. on San Francisquito Canyon Road, which was shut down in both directions afterward, near Rosewood Equestrian.
Two vehicles, a GMC Suburban and a BMW, were involved in the crash and the BMW reportedly caught on fire after the collision.
Three men died - the driver and passenger in the BMW and the driver of the Suburban.
A man and woman were taken to a hospital in critical condition.
Investigators say they believe the white BMW was heading southbound on San Francisquito Canyon when it briefly left the roadway and went onto the shoulder, then overcorrected and swerved into the path of the Suburban heading northbound.
They are looking into whether drugs, alcohol or excessive speed were factors.
Residents say speeding along that stretch of road is common.
"San Francisquito is notorious for people going on canyon runs - they go fast," said Saugus resident Ethan Hagen. "Unfortunately, seeing something like that is not cool, it's not fun. It's sad."