The incident happened just before 2 a.m. on Whittier Boulevard, according to the Los Angeles County Sheriff's Department.
That's when two men entered and tried to rob the store. At some point, a shooting occurred and the security guard was struck by gunfire, investigators said.
When deputies arrived, they found the unidentified victim had been shot in the chest. He was pronounced dead at the scene.
Another employee inside the dispensary at the time was not injured.
It's unclear if anything was stolen, but authorities say the suspects fled the scene in a dark-colored SUV. No arrests have been made.
Meanwhile, another dispensary in Whittier was robbed about half an hour before the East L.A. incident.
The sheriff's department said several masked suspects held the store clerk at gunpoint, smashed display cases before they fled with merchandise and cash in a white Tesla.
It's not clear if the two incidents are related.