The collision, which involved six vehicles, happened at about 1.10am at the entrance to the underpass on Lee Bank Middleway near Edgbaston.
West Midlands Police have warned the road is likely to remain closed “for a very long time”, with detectives describing the circumstances of the “serious collision” as “very difficult and upsetting”.
The force is investigating the cause of the crash.
West Midlands Ambulance Service has described the scene as “extensive and extremely complex”.
A spokesman said a man and woman in the first car escaped with “relatively minor injuries” and were taken to Heartlands Hospital in Birmingham.
The second vehicle, a black cab, was discovered on its side, with the spokesman saying “there was nothing that could be done to save the driver”, who was confirmed dead at the scene.
Two passengers in the back, a man and a woman, were quickly removed by the emergency services.
“Unfortunately, it was not possible to save the woman and she was also confirmed dead at the scene,” the spokesman went on to say.
“The man was taken on blue lights to the major trauma centre at the Queen Elizabeth Hospital Birmingham with the MERIT trauma doctor travelling with the crew. Sadly, he died at hospital.”
In the third car involved in the crash there were four men, three of whom were confirmed dead at the scene.
The other man has been taken to the major trauma centre at the Queen Elizabeth Hospital Birmingham in a critical condition.
Of those travelling in the three other cars, a man and a woman received treatment for minor injuries, another man was discharged after being assessed by paramedics and another said he did not need any assistance.
West Midlands Fire Service said 40 firefighters were sent to the scene in the wake of the “horrific” crash.
“The first West Midlands Fire Service crews arrived in less than four minutes and were met with a complex scene, spread over some distance,” Area Commander Jason Campbell said.
“Our firefighters’ actions involved stabilising vehicles, releasing the dead and injured, as well as administering CPR and first aid.
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“All of the emergency services worked together and co-ordinated their response in extremely challenging circumstances, doing all they possibly could to minimise the loss of life.”