The woman, a pedestrian, had to be freed by firefighters and specialist medics after the crash which happened on Bristol Road in Birmingham at around 4.20pm on Monday.
Four cars were involved in the crash along with the National Express bus which had left the road and crashed into a lamppost next to Selly Oak Railway Bridge.
The bus driver was also assessed by paramedics and taken to hospital but nobody else was injured.
West Midlands Ambulance Service received multiple 999 calls reporting the collision. Paramedics and firefighters worked to rescue the woman, who was underneath the bus.
She was rushed to the Queen Elizabeth Hospital with life-changing injuries.
A spokesman from West Midlands Ambulance Service said: "When the first crew arrived on scene, they found a bus which had been in collision with a lamppost and a pedestrian, who was trapped.
"Several other vehicles had also been damaged in the collision.
"HART paramedics and ambulance crews worked closely with fire colleagues to carefully extricate the woman from beneath the vehicle while she received advanced trauma care.
"The woman, who had sustained life-changing injuries, was taken to Queen Elizabeth Hospital Birmingham for further emergency care.
"The critical care paramedic travelled in the ambulance with the patient to continue treatment on route.
“The bus driver, a man, was also assessed at the scene and conveyed to the same hospital for further checks.”
Photos from the scene showed three cars left damaged next to the 63 bus which ended up diagonal across the pavement next to the damaged lamppost and fencing around a construction site.
Drivers were advised to avoid the road after the crash, near the Heeley Road junction. Buses were diverted near the scene and witnesses have been urged to come forward.
A spokesman for West Midlands Police said last night: "A pedestrian was taken to hospital with serious injuries after the collision, involving a bus and four cars.
"Her injuries are described as serious and the road was expected to be shut for the next few hours."
Three ambulances, two paramedic officers, the Hazardous Area Response Team (HART) and a critical care paramedic attended the scene, with the first arriving within five minutes of the first call at 4.23pm.
A West Midlands Fire Service spokesman added: "We mobilised two fire engines and ten firefighters to this incident after being alerted by the ambulance service. Our first crew arrived in under four minutes.
"The scene presented a number of challenges, as the bus was on an incline and a damaged lamppost was still electrically ‘live’.
"However, using specialist air bags and cutting equipment, our crews were able to help free the casualty by around 4.50pm."
Anyone with information is asked to call West Midlands Police on 101, quoting log number 3494.