The confrontation occurred about 10:45 p.m. near the intersection of Manchester and Belford avenues, a spokesperson for the Los Angeles Police Department said.
The bus driver "heard gunshots from the rear of the bus and immediately stopped, allowing all passengers to exit," said Metro spokesman Jose Ubaldo. "One passenger was found injured and transported to a local hospital, where they later succumbed to their injuries."
According to the LAPD, a fight broke out on the bus between the woman's boyfriend and the suspect. The woman was shot after she brandished pepper spray to intervene in the altercation, police said.
She was transported to a hospital, where she died. Her identity was not immediately released.
The shooter fled the scene and remained at large. The suspect was described only as a 20-year-old man.
An LAPD spokesperson said the incident was being investigated as gang-related.
Anyone with information about the shooting is urged to call Crime Stoppers at (800) 222- 8477.
City News Service contributed to this report.