In 1951 he joined the African National Congress Youth League (ANCYL) and later in 1954 he joined the ANC. During the Congress of the People where the Freedom Charter was adopted he was a branch delegate leader at Kliptown, representing Dube branch where he was a branch secretary. From 1958 to 1960 he was a dedicated and committed ANC and Communist Party functionary. When peaceful means of expressing dissatisfaction with political marginalisation and economic deprivation by the minority regime was barred to the majority Andrew Mlangeni was among the first 6 people to be sent outside the country in 1961 for military training in China.
On his return, late in 1962 he joined the underground unit of Umkhonto Wesizwe (MK) and became a member of the High Command. He was arrested on 24 June 1963 on the national raid day. After 11 July Liliesleaf Farm arrest of 1963, Andrew Mlangeni together with Nelson Mandela, Walter Sisulu, Denis Goldberg and others was proffered with treason charges and later sabotage.
During the trial, some former combatants turned state witnesses and told the court that he was one of the people responsible for recruiting and training an armed force. Before the court passed judgment on him, Mlangeni told the court that:
“Though leaders of many countries throughout the world have tried to persuade the Government to abandon its apartheid policy, and although resolutions have been passed in the United Nations against South Africa, this has met with no result. All that the Government has done is to reply to the people’s demands by putting their political leaders in gaol and breaking up families”.
He was found guilty and sentenced to life imprisonment on Robben Island. He started his life sentence on 12 June 1964.
Life in prison just like out of prison was a terrain of struggle to Andrew Mlangeni and his colleagues. Their right to education while in captivity was the first matter they fiercely took up with their jailors. The regime was too opposed to allow political prisoners to study. However, they fought tirelessly until their right to study was granted in 1967. Andrew Mlangeni completed his matric courses which he started while outside through correspondence.