Chikane led protests at the university against apartheid, which resulted in his leaving the university without a degree in 1975. Chikane was eventually ordained by the church in 1980, when he began advocating social programs such as a soup kitchen and adult education within the church for its primarily African population.

For these actions, Chikane was suspended from the conservative minded AFM in 1981, which would last until his reinstatement in 1990. After suspension from the AFM, Chikane joined the Institute for Contextual Theology, a Christian think-tank inside of the South African Council of Churches which promoted Liberation Theology of which he became the general-secretary in 1987. In 1985, Chikane was one of the leading promoters of the Kairos Document, a leading Christian denunciation of Apartheid.

In late 1989, agents of the apartheid government attempted to assassinate Chikane by lacing his underwear with Paraoxon, two of the suspects being former Police Minister Adriaan Vlok and his then police chief Johan van der Merwe. Each of them received suspended 10-year sentences. Vlok sought forgiveness from Rev. Chikane in 2006 by washing his feet.

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