The Philippine Star reported at least 22 people died and another 20 were injured in the crash in Taguig City.
The newspaper quoted police as saying the bus bound for San Pedro City fell off the road onto a van on the service road of the southbound lane of the South Luzon Expressway.
Most of those killed were passengers in the bus as the van had only two occupants, police said.
Xinhua News Agency quoted a land transport official as saying in a television interview that the van's driver was among those killed while the driver of the bus escaped with injuries.
The condition of those injured was not immediately known.
ABS-CBN News reported the van was crushed after the bus fell on it. The report said the van driver died and his fellow passenger was injured.
The report said investigators were trying to determine what caused the bus to run off the expressway.
Notable deaths of 2014 [PHOTOS]