He was born in Tzaneen, matriculated from Hebron Training College in 1969 and achieved an MSc degree in Applied Mathematics from the University of South Africa (called the University of Azania on the AZAPO website). He joined the South African Students' Organisation (SASO) and was elected onto the Students Representative Council at the University of Zululand in 1971. Moving back to Pretoria, he became chairperson of the SASO Pretoria branch in 1972. He chaired the Botswana region of the Black Consciousness Movement of Azania (BCMA) in 1981 and the BCMA central committee from 1982 to 1994.
He is also the former commander in chief of the Azanian National Liberation Army (AZANLA), the former armed wing of AZAPO.
Mangena returned from exile in 1994 and became leader of AZAPO. He was appointed as Deputy Minister of Education in South Africa by President Thabo Mbeki in 2001, and he became Minister of Science and Technology in 2004.
After the resignation of Thabo Mbeki as President of South Africa in September 2008, AZAPO announced that they withdrew Mosibudi from his ministerial position.