Emergency services, including the Midlands Air Ambulance, were called to the crash on the A5 at around 2.40pm on Thursday afternoon.
The collision involved a Ford Mondeo and an Audi, at the junction of Norton Lane.
One man was airlifted to hospital with serious pelvic injuries. Another man was taken to hospital with a chest injury.
A spokesman for Staffordshire Police said: "Police received a call at around 2.40pm on Thursday reporting a road traffic collision on the A5 in Great Wyrley. The collision involved a Ford Mondeo and an Audi and happened at the junction with Norton Lane.
"The driver of the Audi sustained serious pelvic injuries and was airlifted to the Royal Stoke University Hospital where his condition is described as stable.
"The male passenger of the Mondeo sustained a chest injury and was taken to New Cross Hospital.
"The male passenger of the Audi received minor injuries and was taken to Walsall Manor Hospital as a precaution."