Nsibambi attended King"s College Budo for his high school education. He holds a Bachelor of Science degree in economics, with honors, from the University of London.
He also holds a Masters of Arts degree in political science from the University of Chicago in the United States. His Doctor of Philosophy degree was obtained from the University of Nairobi. Nsibambi served as the dean of Faculty of Social Science at Makerere University from 1978 until 1983 and from 1985 until 1987.
He was director of the Makerere Institute of Social Research from 1994 to 1996.
Between 1996 and 1998, he served as Minister of Public Service in the Uganda Cabinet. In 1998 he was appointed Minister of Education and Sports, serving in that capacity until 1999 when he was appointed Prime Minister and Leader of Government Business.
Nsibambi also served as the chancellor of Makerere University from 2003 until October 2007. He is of the Anglican faith.
He was appointed head of the Department of Political Science at Makerere University in 1987, a position he held until 1990. He tutored at the university in the 1960s, befriending author Paul Theroux, who interviews Nsibambi in his travelogue Dark Star Safari.