Police say the Subaru Forester was travelling south on the northbound carriageway near Watlington, in south Oxfordshire when it hit a Ford Mondeo and a Ford Focus at about 4pm on Monday.
The driver and the passenger of the Subaru, both aged in their 80s, and the driver of the Ford Mondeo, a man in his 30s, died.
Thames Valley said it was investigating the incident, which was captured on another vehicle's dashcam.
Senior investigating officer Sgt Beth Walton, from the Serious Collision Investigation Unit, said: “We are in the early stages of the investigation, in which sadly three people died and our thoughts are with their families.
"We are in the process of contacting witnesses who provided a report to us and are grateful for their support."
Witnesses claimed the vehicle was driving up to 60mph and they were forced to swerve to avoid being hit by the wayward driver.
Oliver Hayes said that it “did not look accidental” when the driver came racing down his lane head-on.
Liz Hindmarsh tweeted: “My husband had to swerve into the middle lane otherwise he’d have been hit by the caravan travelling the wrong way down the M40 in the outside (fast) lane.”
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