Kufuor's public service spans over 30 years. From 1964 to 1969 he was a Kumasi-based private legal practitioner. From 1967 to 1969 he was chief legal officer and city manager of Kumasi. He was a member of the Constituent Assemblies that drafted the Constitutions of the Second and Third Republics respectively. He was a member of Parliament during the Second and Third Republics and served as a deputy minister of foreign affairs during the Second Republic. Kufuor led Ghanaian delegations to the annual meetings of the United Nations general assembly in New York, and the 1970 Ghanaian delegation to Moscow, Prague, and Belgrade. Kufuor returned to private life during the period of military leadership after President Busia's overthrow in 1972 and ran a brick and tile factory. He returned to Parliament in 1979.
Kufuor was a founding member of the Progress Party (PP), the Popular Front Party (PFP), and the New Patriotic Party (NPP). He was the PFP's spokesman for Foreign Affairs and the deputy opposition leader of the PFP during the Third Republic. He was also a member of the parliamentary delegation that visited the United States in 1981 for talks with the officials of the International Monetary Fund (IMF) and the World Bank on Ghana's economic problems.
After the overthrow of the Limann government by Flight Lieutenant Jerry Rawlings in 1981, Kufuor was appointed the minister for local government with the PNDC. However, Kufuor and Rawlings had difficulty establishing rapport, and Kufuor resigned from the Rawlings government after seven months citing "irreconcilable political differences." In 1996, Kufuor ran in the presidential elections as a candidate of the NPP party, losing to incumbent president Jerry Rawlings. He again ran for the presidency on 7 December 2000, this time winning the second round of voting with 56.7% of the vote. He took office on 7 January 2001.