Emergency services were scrambled to the Enyobeni Tavern, in the Scenery Park township, early on Sunday morning. They found a number of bodies, with several others reportedly injured.
Relatives have not yet been given permission to see the bodies, according to local reports, and have been calling out the names of dead loved ones.
After initial conflicting reports of the death toll, health officials have confirmed they believe at least 22 people have died.
The cause of the tragedy is not yet known, but there are reports that a poisonous substance, a gas leak, or possibly a stampede at the tavern could be to blame for the deaths.
South African news service Daily Dispatch said the bodies were lying in the venue on chairs, with “no obvious sign of injury”.
The South African Police Service (SAPS) has launched an investigation into the incident, and claimed that it did not wish to speculate until its enquiries were complete.
Brigadier Tembinkosi Kinana told TV channel Newzroom Afrika: “The SAPS confirms an incident where people were found dead in a tavern in Scenery Park in the area of East London.
“We received this report in the early hours of Sunday. The circumstances surrounding the incident are under investigation as we speak.
“We do not want to make any speculation at this stage, our investigation is continuing.”
Despite officials initially reporting that the victims were between 18 and 20, News24 has cited police minister Bheki Cele as saying the youngest victim is just 13 years old.
Addressing families outside the Brookwood Mortuary, he said people between the ages of 13 and 17 had died at the Scenery Park tavern.
Cele, who reportedly cried after seeing the children’s bodies at the mortuary, said: “The scene I have seen inside, it doesn’t matter what kind of a heart you have, you will be said.
“Firstly, the sight of those bodies sleeping there but when you look at their faces you realise that you’re dealing with kids.
“You’ve heard the story that they are young but when you see them you realise that it’s a disaster.”
Eastern Cape police commissioner Nomthetheleli Lilian Mene told SABC there had been an “alleged stampede” inside the tavern.
Siyanda Manana, a spokesperson for the Eastern Cape provincial health department, said the bodies would be transported to state mortuaries, where relatives are expected to help identify both male and female victims.
“We are going to immediately be embarking on autopsies so we can know the probable cause of death,” he told reporters, as forensic personnel continued their work at the cordoned-off scene at the tavern.
“We are talking 22 bodies right now,” Manana added.