State broadcaster SABC reported the deaths resulted from a possible stampede at Enyobeni Tavern but was scant on details as the exact cause of death remained unknown.
The bodies were taken to state mortuaries where relatives are expected to help identify both male and female victims, said Siyanda Manana, a spokesperson for the Eastern Cape provincial health department.
"We are talking 22 bodies right now," Manana said, adding that toxicology tests were part of the examination.
"We are going to immediately be embarking on autopsies so we can know the probable cause of death," he told Reuters as forensic personnel continued their work at the cordoned-off crime site.
A 17-year-old girl, who only gave her name as "Lolly" and lived close to the tavern, told Reuters the venue was a popular hangout with teenagers, but the community wanted it shut down after the tragedy.
"Everyone wants it closed down because they sell alcohol to under-age children. Everyone is angry, everyone is sad because of what happened," she said.
Expressing his condolences to affected families, President Cyril Ramaphosa said he was worried about the circumstances under which young people, potentially under the age of 18 years, were allowed to gather at the tavern. Ramaphosa said in a statement the law must take its course once investigations conclude.
Bheki Cele, the national police minister, told a large crowd in Scenery Park during an impromptu visit broadcast live on television "The call is on the parents to see that their kids are kept well, the call is on the community to say we can't allow our kids to die,"
"What has happened can be equated to a massacre," East London mayor, Xola Pakati said in a statement.