Details are only emerging of the incident, but Michael Sun, MMC for public safety for the City of Johannesburg, confirmed to News24 that there had been fatalities.
The incident took place at Gate J at the stadium and although the reason for the stampede is unknown, it was reportedly due to the sale of fake tickets at the stadium.
"As sponsors of the Carling Black Label Champion Cup, we are saddened by the fatalities that occurred late this afternoon due to a number of people who attempted to push through the stadium gates," a statement from Carling Black Label said.
"As things stand at the moment, we can confirm two fatalities caused by blunt force trauma, one critically injured and sixteen spectator with minor injuries.
"This incident is extremely unfortunate as solid security plans were put in place in conjunction with SAPS and various other stake holders, to ensure that this is a risk-free event.
"Since the inception of the Carling Black Label Cup in 2011, we have had record attendance and incident free events.
"The South African Police Services and Stadium Management South Africa are working together to investigate this matter.
"As Carling Black Label, Kaizer Chiefs, Orlando Pirates and SMSA - We wish to express our sincere condolences to the families of those affected by the incident.
"We will endeavor to keep the public informed as we receive progress on the matter."
The game continued despite the deaths, but it is another dark stain in the history of the Soweto Derby.
In 1991 a total of 42 people died at the Oppenheimer Stadium in Orkney after a stampede during a friendly between Chiefs and Pirates, while 10 years later 43 people died at Ellis Park when there was a crush as fans tried to enter a venue that was already full to capacity.