Boesak first became known as a liberation theologian, starting with the publication of his doctoral work (Farewell to Innocence, 1976). For the next decade or so, he continued to write well-received books and collections of essays, sermons, and so on.
Boesak was elected as president of the World Alliance of Reformed Churches in 1982, a position he held until 1991.
He rose to prominence during the 1980s as an outspoken critic and opponent of the National Party's policies and played a major anti-apartheid activist role as a patron of the United Democratic Front (UDF) from 1983 to 1991. In 1991, Boesak was elected chairman of the Western Cape region of the African National Congress (ANC).
In 2008, Boesak publicly challenged the South African leadership to remember why they joined all races to create a non-racial South Africa. In the annual Ashley Kriel Memorial Youth Lecture, Boesak suggested that the ANC was well down the slippery slope of ethnicity preferences and "had brought back the hated system of racial categorization."
Also in 2008, while serving as the Moderator of the Cape Synod of the Uniting Reformed Church in Southern Africa, Boesak, to the shock of many senior church leaders, announced that he would resign all of his positions within the church because of the church's discriminatory position on homosexuality and gay and lesbian persons. Boesak invoked the anti-apartheid 1986 Belhar Declaration, which lambasts all forms of discrimination, to say that the church should welcome gays and lesbians and begin to perform gay marriage ceremonies and appoint gay clergy. Dr. Boesak had originally come out in favour of same-sex marriage in 2004, a year before South Africa's Constitutional Court ruled that the denial of marriage rights to gay people was discriminatory and violated the country's constitution.
In December 2008 he left the ANC to join the Congress of the People party. The same month saw Boesak voicing his views on the Zimbabwe crisis, calling on citizens of the stricken country to rise up in opposition to President Robert Mugabe and his authoritarian ruling party. He also censured Mbeki for failing in his role as the Southern African Development Community's official mediator to heed the churches' call for a peace-keeping force.
He also called for a revaluation of affirmative action, describing as "totally inexcusable"its effectuation in the Western Cape.
In June 2013, Christian Theological Seminary and Butler University in Indianapolis, Indiana appointed Boesak as The Desmond Tutu Chair for Peace, Global Justice, and Reconciliation Studies, a new four-year position held jointly with both institutions.