Police believe the B-double truck collided with a school bus at the intersection of Hamilton Highway and Dundas Street in Inverleigh, 28km west of Geelong, just before 8am.
The truck then rammed into a nearby house, causing significant damage.
The male bus driver was airlifted to the Royal Melbourne Hospital with lower body injuries.
The truck driver, a 28-year-old man from Tyntyndel, managed to escape without any injuries.
There were no passengers on the school bus and no one was inside the house at the time of the crash.
Police are continuing to investigate the incident.
Anyone who witnessed the collision or with dashcam footage is urged to contact Crime Stoppers on 1800 333 000.