Wake County officials tell ABC11 Eyewitness News that a Buick sedan crossed the center line and ran into the front of the bus.
School bus number 547 was transporting students home from Holly Ridge Middle School when the accident happened.
"I just heard people like, 'oh my God,'" student Jawad Malik said. "We like slammed against the seat and turned around and I just saw smoke coming out."
Officials say about 40 kids were on board. Six students were taken to the hospital for observation --two to WakeMed of Apex and four to WakeMed of Cary with non-serious injuries.
"We weren't sure how many people on board the bus were going to need transport," said Mark Andrews with the Town of Holly Springs.
Authorities say the two people inside the Buick were taken to WakeMed of Raleigh with serious injuries.
The driver of the Buick, 19-year-old Thomas Caso is in serious condition. The name and condition of the passenger in the car with Caso has not been released.
They also say a driver in another car that was apparently clipped by the Buick was taken to the hospital with minor injuries.
When Chopper11 HD arrived at the scene, the remaining students that were on the bus were waiting on the side of the road until another school bus was able to transport them home. Some parents even came to pick up kids from outside the Arbor Creek Subdivision where they were waiting.
"I'm rushing from Raleigh, from my job," concerned parent Maria Connochie said. "I'm sure he's okay. They said there were minor injuries, but I don't know."
Concerned parent Mary Williams also showed up, hoping to pick up her son, who called her moments after the accident happened.
"I was like okay, 'are you okay, are you and the kids alright,'" Williams said. "He said, 'we're fine, everybody's fine. I don't know about the other car though.'"
Police continue to investigate what caused the accident.