The incident occurred shortly before 9:15 a.m. on Interstate 5 in Carlsbad as the truck was heading from San Diego to an office of the Federal Deposit Insurance Corp., authorities said.
"One of the doors popped open and bags of cash fell out," California Highway Patrol Sgt. Curtis Martin said.
Several bags broke open, spreading money - mainly $1 and $20 bills - all over the lanes and bringing the freeway to a chaotic halt, Martin said.
Video posted online showed some people laughing and leaping as they held wads of cash.
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Two people were arrested at the scene, and Martin warned that any others who are found to have taken the money could face criminal charges. He noted there was plenty of video taken by bystanders at the scene and that the CHP and FBI were investigating.
Anyone who took money was urged to bring it to the CHP office in Vista.
Authorities didn't immediately say how much money was lost. However, at least a dozen people had returned money they collected to the CHP by Friday afternoon, the San Diego Union-Tribune reported.
"People are bringing in a lot," Martin said. "People got a lot of money."
The freeway was reopened shortly before 11 a.m.