The crash was reported at 3:12 a.m. on southbound Highway 880 just north of Washington Avenue, CHP Officer Ralph Caggiano said.
The woman's name is being withheld because her family has not been notified of her death, according to the Alameda County coroner's bureau.
The woman was traveling south on the highway in a 2010 Subaru when, for an unknown reason, she veered to the left and crashed into the concrete center median.
The Subaru then traveled to the right across all lanes of traffic and crashed into attenuator barrels on the right shoulder before spinning out and coming to rest in the roadway, according to the CHP.
A 2006 Ford driven by a 35-year-old Hayward man then struck the Subaru, as did a 2008 Toyota driven by a 54-year-old Hayward man.
The woman in the Subaru was pronounced dead at the scene. The drivers of the other two cars were uninjured, the CHP said.
The cause of the crash is under investigation.