In 1951, Joseph took a job with the Garment Workers Union, led by Solly Sachs. She was a founder member of the Congress of Democrats, and one of the leaders who read out clauses of the Freedom Charter at the Congress of the People in Kliptown in 1955. Appalled by the plight of black women, she was pivotal in the formation of the Federation of South African Women and with the organization's leadership, spear-headed a march of 20,000 women to the Union Buildings in Pretoria to protest against pass laws on August 9, 1956. This day is still celebrated as South African Women's Day.
She was a defendant at the 1956 Treason Trial: she was arrested on a charge of high treason in December 1956 then banned in 1957. On the October 13, 1962, Joseph became the first person to be placed under house arrest under the Sabotage Act that had just been introduced by the apartheid government. She narrowly escaped death more than once, surviving bullets shot through her bedroom and a bomb wired to her front gate. Her last banning order was lifted when she was 80 years old.
Joseph had no children of her own, but frequently stood in loco parentis for the children of comrades in prison or in exile. Among the children who spent time in her care were Winnie and Nelson Mandela's daughters Zinzi and Zenani and Bram Fischer's daughter Ilsa.
Joseph died on December 25, 1992, at the age of 87.
- The road, formerly known as Davenport Road, in Glenwood, Durban has now been named after Helen Joseph under the recent Road Name Change Act which was initiated by the South African government in 2007 to rename streets which have names linked to pre-1994 colonialism.
- Helen Joseph Hospital in Johannesburg has been named after Helen Joseph.
- A student residence at Rhodes University (Grahamstown, South Africa) is named after Helen Joseph.