The school bus, which was blocks away from its first pickup of the day, had no children on board at the time of the crash, Baltimore Police spokesman T.J. Smith told reporters.
"It literally looks like a bomb exploded in the bus," he said. "It is catastrophic damage."
The school bus rear-ended a car, then sideswiped a cemetery pillar near the road, then crossed into oncoming traffic and collided with the commuter bus around 7 a.m., Smith said.
Shawn Braxton, who was driving the car that the school bus hit, told CNN affiliate WBAL
that he didn't know how he survived the crash.
He had stopped in his Ford Mustang to make a turn Tuesday morning when the bus hit him from behind, according to his wife.
"Physically, I'm bruised and banged up," Braxton told WBAL. "Mentally, it's going to take awhile to get myself together."
Video from WBAL shows the school bus wedged into the side of the commuter bus, with firefighters surrounding the scene.
The school bus driver and five people aboard the commuter bus were killed, Smith said. Rescuers transported 10 people to local hospitals with injuries. Investigators are working to pinpoint what caused the crash.
An aide who was on the school bus and survived the crash may be able to help investigators shed light on what happened, Smith said.
There were no skid marks in the road, Smith said, "so something catastrophic took place, and it's something we're continuing to investigate."
Thursday, authorities said the school bus driver who died in the crash was not authorized to operate the vehicle.
The driver, who drove the school bus as an employee of AA Affordable Transportation, a contractor for the school district, had failed to provide an updated Medical Examiner's Certificate required by federal regulations.
The medical certificate expired in late August.
The company did not comment when contacted Thursday by CNN.