The incident was reported around 10:45 p.m. Thursday at the intersection of Western Avenue and Olympic Boulevard, according to the Los Angeles Police Department.
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Details were limited but police said some kind of altercation broke out on the bus and that's when the suspect, described as a man in his 30s, used pepper spray on the victim.
The suspect took off and the victim was pronounced dead at the scene.
It's not clear if the suspect and victim knew each other, or how many other people were on the bus at the time.
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Pepper spray is known as a non-lethal form of defense. A detective at the scene told Eyewitness News the medical examiner will be able to answer questions as to how exactly the victim died.
In a written statement, Metro said both of the men were passengers and that the cause of death is not yet known.
"Metro is working closely with the Los Angeles Police Department as they investigate this incident. Safety is our number one priority and over the past year Metro has seen an overall, month-over-month reduction in serious crimes on our transit system due to our multilayered public safety plan, which includes the addition of Transit Security Officer and law enforcement bus riding teams on key Metro bus lines. However, one crime is too many and will not be tolerated."
Bus riders say they've seen aggressive behavior before on the bus and try to stay away from it.
"Don't give the other person energy," a man named Darin told Eyewitness News. "The moment you start fighting back... you just don't know how far they're willing to take it. If you keep going along with the person... you could be outside the bus and fist fighting with somebody for no reason at all."