Three vehicles were involved in the accident on Belgrave Middleway, near Edgbaston, at about 01:00 GMT.
Three men in one car died at the scene and a fourth is critically injured in hospital. The driver of a taxi and his two passengers were also killed.
West Midlands Police described dealing with the wreckage as "very difficult and upsetting" and said officers were investigating how the crash happened.
The road has been closed and police have appealed for witnesses.
The first car in the crash had suffered extensive damage but, "astonishingly", the man and the woman inside managed to get out with relatively minor injuries, an ambulance service spokesman said.
"The second vehicle, a black cab, was on its side. Sadly, there was nothing that could be done to save the driver and he was confirmed dead at the scene."
The taxi driver has been named locally as father of six Imtiaz Mohammed, who worked for Castle Cars.
The female passenger was also confirmed dead at the scene, while her male companion died at Queen Elizabeth Hospital.
There were four men in the third car, and all had been thrown from the vehicle, the ambulance spokesman said.
"Tragically, three of them were confirmed dead at the scene."
The fourth was taken to the Queen Elizabeth Hospital and is in a critical condition.
Three other cars were caught up in the crash and suffered minor damage trying to avoid it.
Michelle Brotherton, from the ambulance service, said her staff had dealt with 13 patients in total.
As well as those who died and the man in a critical condition, four people were taken to Heartlands Hospital where their condition is believed to be non-life threatening.
A further two patients were "discharged on scene".
Police, @WestMidsFire & @OFFICIALWMAS are responding to a very serious crash on Lee Bank Middleway in Edgbaston, Birmingham near to the tunnel which goes beneath Bristol Street. Call received at 1.11am Sun 17/12. Avoid area. Road will be closed for a very long time.
— West Midlands Police (@WMPolice) December 17, 2017
Supt Sean Phillips said the police officer in charge of the investigation had described the wreckage as "very harrowing".
He said it was "too early" to speculate on the cause of the accident.
"It will take some time to unpick and just understand exactly what's happened. It would be unfair for me to speculate at this time," he said.
He confirmed the road had been gritted at 17:00 GMT the previous evening.
At the scene: Riyah Collins, BBC West Midlands
Metres of police cordon tape and a number of vehicles have been used to seal off the road, and blue forensic tents can be seen below in the underpass.
The cordon stretches at least 100 metres either side of the Middleway and I can see numerous police officers.
As locals find out what happened, they all say how tragic it is that six people should die so close to Christmas.
It is not yet known what caused the crash, but people are telling me there has long been a problem with speeding and racing on this road and the adjoining Bristol Street.
A car involved in a separate crash nearby just a week ago is still on the side of the road.
The accident happened below the underpass on the A38/Bristol Road, where Belgrave Middleway meets Lee Bank Middleway.
The stretch of road from Islington Row to Bristol Street has been closed and is likely to remain so throughout Sunday, police said.
One resident who lives opposite said she woke at about 02:00 and saw the emergency crews.
"This road is really dangerous. Young kids like to challenge themselves and go really fast," she said.
"I can't believe six people have died, and so close to Christmas and New Year."
The road has two lanes either side and a 40mph speed limit.
Area Commander Jason Campbell, of West Midlands Fire Service, described it as a "horrific" incident.
He said the crash site was complex and "spread over some distance".
Any witnesses have been asked to contact West Midlands Police.
All first responders at the scene are doing their very best in very difficult and upsetting circumstances. This is a very serious incident. If you saw the crash happen or the circumstances leading up to it, please call us now on 101.
— West Midlands Police (@WMPolice) December 17, 2017
