Most will work in shelters, giving comfort to displaced residents, and helping with feeding and moving supplies, among other duties.
"Hurricane Matthew is an extremely dangerous storm," Bill Earley, regional chief executive officer for the American Red Cross of San Diego/Imperial Counties said. "Hurricane Matthew could leave widespread devastation in its wake and untold amounts of need for food, shelter and help."
Due to airport closures, most volunteers from San Diego will fly to South Carolina and be re-assigned throughout the affected area as needed.
"This is a time for neighbors and communities to come together and support one another," Earley said. "We are one Red Cross and are proud to help our sister regions throughout this disaster response."
More than 27,000 people spent Thursday night in 198 Red Cross and community evacuation shelters in Florida, Georgia and South Carolina. That number was expected to grow.
In addition to shelters, the Red Cross has more than 1,800 disaster workers and 90 response vehicles ready to help in the affected states and more help is standing by.
The Red Cross has also positioned more than 30 trailer loads of shelter supplies, ready-to-eat meals, clean-up and comfort kits.