The bus, which appears to have been travelling south, is upright, but on a lean.
There are multiple emergency services at the scene, including at least six police cars, two fire engines and an ambulance. Two ambulances have already left the scene.
St John said it has dispatched two helicopters.
People sitting in the queue of traffic, which is at least 1km long on the north side of the crash, have been told the road may be closed for up to five hours.
The New Zealand Transport Agency said the highway was closed, near Allandale Rd, south of Kingston following the crash.
A worker from Kingston Corner Cafe and Bar, which sits on State Highway 6, said staff noticed police and fire engines with sirens and lights on at 7.55am. They were heading southbound from Kingston, the worker said.
The accident follows another crash involving a car and a bus carrying 14 tourists near the Devil's Staircase south of Queenstown two weeks ago in which one person died.
The bus operator in that accident, Southern Discoveries, said the driver of the car died at the scene.