Television stations RTL and RTBF said the Polish-registered bus was carrying around 40 Ukrainians and Russians aged between 15 and 17 years old.
The accident occurred on a highway heading toward Anvers, police told the Belga news agency.
Three adolescents died as well as the driver and a chaperone, according to the latest toll released by Belgian media.
The immediate cause of the crash, which left the bus lying on its side, was unknown, Belga said.
The most seriously injured were evacuated to different hospitals in the region.