It happened around 9:30 a.m. at the intersection of Market Street and Schuylkill Avenue, just steps away from 30th Street Station.
Officials say the 39-year-old man, who uses a wheelchair, was panhandling in front of the federal building.
Police say a Peter Pan bus, which was en route to Washington DC and had about 30 people on board, had a green light going north and that the bus driver did not see the man in the wheelchair in the middle of traffic.
Officials say the victim was trying to beat traffic to the median when he was struck.
He was pronounced dead at the scene.
One of the man's friends, who is often out in the area panhandling with him, says he is devastated.
"He was a really good man," said the victim's friend, Brenden Nieves. "Even though I only knew him for a few months, I didn't really know a guy like him. Very nice man."
The crash investigation division is on the scene.
Police have not released the victim's name.
Action News is working to reach the bus company for comment.