The accident involved two cars – a Vauxhall Astra and a Honda Jazz – and happened on the A85 at around 9.30pm on Monday.
Emergency services attended and the driver and passenger of the Vauxhall Astra were taken to Ninewells Hospital.
The 22-year-old driver is in critical condition and the 18-year-old passenger has been described as stable.
The other car had a seven-year-old passenger and was being driven by a 32-year-old woman, both were taken to hospital to be checked over.
The road was closed to allow a collision investigation to be carried out and re-opened at 7.30am on Tuesday, December 7, 2021.
Police Scotland is now appealing for information to establish exactly what happened to cause the crash.
The force is asking anyone who was in the area at the time to get in touch as soon as possible.
Sergeant John Learmonth, from Perth Road Policing Department, said: “Our investigation into this collision is continuing and I would appeal to any witnesses who have not yet spoken to police, or anyone with information, to contact us.
“I would also ask anyone driving on this road at the time of the crash or just before it took place who has dash-cam footage to speak to officers as this may assist our inquiry.”
If you have any information you should contact police on 101 and quote incident number 3334 of December 6, 2021.