While at Oxford, Nkangi studied law at Lincoln's Inn of Courts in London, then returned to Uganda in 1960 where he set up his law practice. He also joined pre-independence Ugandan politics. He formed a political party called the "United Party"; later called the "United National Party". In 1962, he abandoned the UNP and joined the Kabaka Yekka political party. He was elected to represent Masaka East Constituency in the Ugandan Parliament, in May 1962. Following independence on 9 October 1962, Nkangi served as minister without portfolio in the ministry of economic affairs. Then as the commerce and industry minister. On 17 August 1964, Nkangi, at age 33 years and a bachelor, was elected Buganda's katikkiro by the Lukiiko in a landslide. Looking back, Nkangi says his humble beginnings must have marketed him. "The Kabaka did not know me personally." Trouble started in early 1966. On 15 April 1966, the 1962 Uganda constitution was abrogated during a parliamentary session in which Milton Obote, the then prime mister, was surrounded by Uganda Army troops. The Buganda lukiiko passed a resolution to eject the central government from Buganda; essentially declaring Buganda's secession from Uganda. In response, Obote ordered Idi Amin, the army commander at the time to attack the Kabaka's palace at Mengo. The assault came on 24 May 1966. Both Muteesa and Nkangi fled to the United Kingdom. Nkangi went via Nairobi, in Kenya. In 1967, Obote abolished the cultural kingdoms and put a new constitution in place.
Exile
While in exile, he was able to find work as a research fellow at Lancaster University. Also while there, he was able to witness the Kabaka's written desire to have his son Ronald Muwenda Mutebi succeed the Buganda throne, when that time came. After Muteesa passed away on 21 November 1969, Mayanja Nkangi, in his capacity as Katikkiro, proclaimed the death, as is the custom. He returned to Uganda in April to arrange and partly oversee the deceased king's funereal in April 1971.
After exile
Following the removal of the Obote I regime in 1971, Nkangi returned to Uganda and re-opened his law practice. Although Amin spied on him, he generally left him alone, once he learnt that Nkangi had no plans to undermine his government. Following the overthrow of Idi Amin in 1979, Nkonge formed the Conservative Party. When the Obote II government was overthrown by the military junta led by Tito Okello Lutwa, Nkangi was appointed minister of labour, serving in that capacity from August 1985 until January 1986. Under the National Resistance Movement administration, led by Yoweri Museveni, Nkangi served as minister of education, minister of planning, minister of finance and ministry of justice. His tenure in Museveni's cabinet lasted from 1986 until 2001. After his retirement from cabinet, he was appointed chairman of the Uganda Land Commission, serving in that capacity from 2002 until 2012. In 2010, he was appointed Chairman of the Uganda Land Commission, which he held from 2010 until 2013. In later life, he wrote an autobiography, titled "Out of Empire into Servitude."
