A police spokeswoman said the crash happened just after 10am south of Fairlie.
A St John Ambulance spokesman said one person suffered a serious head injury in the crash and was being flown to Dunedin Hospital by rescue helicopter.
Two others suffered moderate and minor injuries and were taken to Timaru Hospital for treatment.
A further 11 people on the bus were assessed at the Fairlie Ambulance Station but did not require treatment, the spokesman said.
The Geraldine Fairlie Highway remains partially blocked near Mt Michael and Pusey Rd, where the bus ran off the road, toppling over on its side.
The police spokeswoman said eyewitnesses reported the bus lying half in and out of the ditch on its side.
The highway between Geraldine to Fairlie was now down to one lane and motorists were warned to take extra care near the Mt Michael Valley Rd intersection.
