The most seriously injured victim, a woman in her 60s, was rushed to hospital.
Paramedics, police and firefighters attended the scene after reporting a collision at 6:40 p.m.
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A North West Air Ambulance Service helicopter also visited the scene, landing on the grounds of the nearby Aigburth Cricket Club.
A tent had been erected near the crash site and the road is expected to remain closed for some time.
A spokeswoman for Merseyside Police said: ‘At 6:40 p.m. it was reported that a car had collided with a tree on Aigburth Road.
“Emergency services are present and the four occupants of the vehicle will be taken to hospital for evaluation.
“The condition of an occupant, a woman in her sixties, is described as critical.
“Roads are currently closed and motorists are urged to avoid the area.”
Anyone who has witnessed the incident, or has information, is asked to contact @MerPolCC, 101 citing ref. 854 of 20/9/20 or the road police unit on 0151 777 5747.
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