He said the current government was worse than the apartheid state.
The ANC, which liberated South Africa from white minority rule in 1994, suffered its worst ever electoral performance in August.
Mr Mthembu said he excluded no-one in the leadership from his call for resignations – not even himself.
“President Jacob Zuma is the president of the ANC (African National Congress),” he told ENCA television.
“When I said the entire ANC leadership that has already taken collective responsibility must take the fall, I meant everybody, myself included, including President Zuma.”
Quizzed by local journalists on the comparison to the apartheid state, he said it had also used “state instruments” to suppress the people.
However, he said even the apartheid regime “never pursued its own ministers”.
“Perhaps we are not the leadership that can take the ANC forward under these conditions,” he said.
Since taking office, Finance Minister Pravin Gordhan has attempted to distance himself from Mr Zuma’s business allies.
However, he is now facing allegations of misconduct from when he was in charge of the tax collection service a decade ago.
The fraud charges relate to alleged severance payments made to two senior executives at the South African Revenue Service (SARS).
Mr Gordhan is also supported by the party’s deputy president, Cyril Ramaphosa.
There have been growing rifts within the ANC in recent months.
In the August elections, the party suffered its worst results since the election of Nelson Mandela in 1994, losing several key battlegrounds.
Voters were seen as reacting to high unemployment and the scandals surrounding President Jacob Zuma.