The Orillia OPP say one person has died and another person has been transported from the scene, via air ambulance, to a Toronto area trauma centre with serious injuries.
Two other occupants were transported to a local hospital for treatment.
The OPP say the two-vehicle collision at Highway 12 at Sturgeon Bay Road occurred at about 7:30 a.m.
Names of the victims are being withheld until family is notified.
OPP Central Region traffic reconstruction members are on scene assisting with the investigation.
The intersection of Sturgeon Bay Road/Vasey Road and Highway 12 will remain closed for several hours. Motorists are asked to avoid the area until further notice.
Police have also closed the off-ramps at Vasey Road from Highway 400 to assist with traffic
The Orillia OPP and other emergency services personnel are investigating a "serious collision" that has shut down Highway 12 this morning.
Police, in a Tweet, said Air Ornge was attending the scene with its helicopter.
A reporter at the scene said it appears the crash involved two vehicles: a pickup truck that is now in the ditch and a mini-van that remains in the intersection. Both vehicles are badly damaged.
As of 8:45 a.m. Highway 12 at Sturgeon Bay Road was closed in both directions.
Police are asking people to avoid the area and say more information will be provided when it's available.