He was born in Engcobo in the homeland of Transkei. Educated in a local missionary school, he left in 1926 to work. He moved to Johannesburg in 1928 and experienced a wide range of manual jobs. He joined the ANC in 1940. In 1943, together with Nelson Mandela and Oliver Tambo, he founded the ANC Youth League, of which he was initially the treasurer. He also had a prominent planning role in the militant Umkhonto we Sizwe ("Spear of Africa"). He was made secretary general of the ANC in 1949, displacing the more passive older leadership, and held that post until 1954.
As a planner of the Defiance Campaign from 1952, he was arrested that year and given a suspended sentence. In 1953, he travelled to Europe, the USSR, and China as an ANC representative. He was jailed seven times in the next ten years, including five months in 1960, and was held under house arrest in 1962. At the Treason Trial (1956 - 1961), he was eventually sentenced to six years, but was released on bail pending his appeal. He went underground in 1963 but was caught at Rivonia on July 11. At the conclusion of the Rivonia Trial (1963 - 1964), he was sentenced to life imprisonment on June 12, 1964. With other senior ANC figures, he served the majority of his sentence on Robben Island.
In October 1989, he was released after 26 years in prison, and in July 1991 was elected ANC deputy president at the ANC's first national conference after its unbanning the year before. He remained in the position until after South Africa's first democratic election in 1994.
In 1992, Walter Sisulu was awarded Isitwalandwe Seaparankoe, the highest honour granted by the ANC, for his contribution to the liberation struggle in South Africa.
Walter Sisulu was given a "special official funeral" on 17th May 2003.