The crash involved a car and ute on State Highway 1 near Mosgiel.
A Fire and Emergency spokeswoman said crews from Mosgiel, St Kilda and Lookout Point stations were called to the scene, near the Saddle Hill Overpass, about 3.30pm.
There was no one trapped, but fire crews said they assisted St John ambulance staff to treat four people with moderate to minor injuries.
Police said the crash closed SH1 between the Quarry Road Bridge and Saddle Hill Overpass.
By 5.15pm, motorists were reporting on social media that traffic remained backed up and it was "very slow" going.
An Otago Daily Times reporter at the scene said the ute had knocked over part of the wire median strip in the centre of the road and stopped in the inner verge of the northbound lane.
The car lay further up the highway, across one southbound lane and the outer verge of the motorway.
Traffic heading south was backed up about half a kilometre and traffic in the northbound lane was down to one lane for a time.
Dozens of vehicles had parked up at the motorway lookout at the intersection of Coalstage Rd and Morris Rd to look at the scene.
Police said about 6pm the road was now clear.
