Motlanthe was politically active from an early age. He worked for the Johannesburg city council when he was in his early 20s, and it was there that he was recruited into Umkhonto we Sizwe (“Spear of the Nation”), the militant wing of the African National Congress (ANC). In 1976 he was jailed for 11 months for furthering the aims of the ANC, and he was found guilty of terrorism the following year. He was sentenced to a term of 10 years at Robben Island, the prison where Nelson Mandela (Mandela, Nelson) had been incarcerated since 1964.

Upon his release in 1987, Motlanthe joined the National Union of Mine Workers as education secretary and in 1992 became its general secretary. Among his achievements were the creation of pension and education funds, as well as the enactment of a new wage scale that would soften the financial blow to mine workers when ore and diamond prices dipped. When the ANC was legalized in 1990, Motlanthe was tasked with the establishment of the organization in the Pretoria area, and he served as its first local chairperson. In 1997 he was elected secretary general of the ANC. During this time, Motlanthe served as a sort of ambassador for the ANC, both within South Africa and abroad.

In December 2007 Motlanthe was elected deputy president of the ANC, and Pres. Thabo Mbeki (Mbeki, Thabo) appointed him minister without portfolio in July 2008. In the heated party leadership contest between Mbeki and Jacob Zuma (Zuma, Jacob), Motlanthe emerged as a figure whose loyalty to the ANC was respected by both factions. When Mbeki stepped down in September 2008 amidst accusations of political interference in the government's corruption case against Zuma, Motlanthe was chosen to be interim president until elections could be held in 2009.