Two people have been assessed by paramedics at the scene of the crash with one male in his 30s transported to Ballarat Base Hospital in a serious but stable condition.
An Ambulance Victoria spokesperson said the man suffered injuries to to arm, leg and head and has been taken to the hospital for further assessment.
A female in her 50s was assessed at the scene but was found not top be in need of transport to a hospital.
A car roll-over in Clarendon has closed the Midland Highway between Clarendon and Scotsburn while three people are assessed for injury.
Emergency services were called to the scene tat 11.02 today to calls of people trapped in their cars at the accident site.
A spokesperson for Ambulance Victoria said paramedics are assessing three people for injury after one car rolled into the path of another car on the highway.
It is understood a male in his 50s has suffered injuries to his arm and head while a female also in her 50s and another unknown patient are currently being assessed for injuries.
The road remains closed to traffic and commuters are advised to avoid the area if possible.