Meles was born in Adwa, Tigray in Northern Ethiopia, to an Ethiopian father from Adwa, Ethiopia, and a mother from Adi Quala, Eritrea. He graduated from the General Wingate high school in Addis Ababa, then studied medicine at Addis Ababa University (at the time known as Haile Selassie University) for two years before interrupting his studies in 1975 to join the TPLF. While a member of the TPLF, he founded the Marxist-Leninist League of Tigray. His first name at birth was "Legesse" (thus Legesse Zenawi, Ge'ez: ለገሰ ዜናዊ legesse zēnāwī) but he is better known by his nom de guerre Meles. He later changed his first name to "Meles" in honor of a University student and a revolutionary radical who was executed by the previous government in 1975.
The TPLF was one of many armed groups struggling against the dictator, Lieutenant Colonel Mengistu Hailemariam. Zenawi was elected Leader of the Leadership Committee in 1979 and Leader of the Executive Committee in 1983. He has been the chairperson of both the TPLF and the EPRDF since the EPRDF assumed power at the end of theEthiopian Civil War in 1991. He was president of the Transitional Government of Ethiopia (TGE), during which Eritrea seceded from the country and the experiment of ethnic federalism started.