The crash happened around 2.30am on Friday on southbound I-95 in Stafford County, near Quantico. All five who died were in vehicles hit by the bus, and 44 people were taken to hospital, including three in critical condition, police said.
"The preliminary investigation indicates that traffic was slowing southbound for an upcoming work zone," state police said in a news release.
"A bus failed to slow for traffic and struck six vehicles."
Police said there were approximately 34 passengers on the bus.
"We've got patients in multiple hospitals. We've got the driver at a hospital here," said Peyton Vogel, a Federal Transit Administration spokesperson who was on the scene.
"I've got to say, this is one of the most tragic things I've ever seen. Absolutely tragic."
Four of the fatalities were in one car, which caught fire. The fifth victim was in an SUV that was struck by the bus.
State police identified the bus driver as Jing S Dong, 48, of Staten Island, New York. Charges are pending, authorities said.
The National Transportation Safety Board posted online that it was sending a "go-team" to conduct a safety investigation into the crash and that it would have a spokesperson at the scene.
The southbound lanes had reopened by midday, but traffic was still backed up for a several kilometres, according to a state transportation advisory.
While it is too soon to say what caused Friday's crash, federal authorities have been grappling with interstate passenger bus safety issues for decades.
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