Meles was born in Adwa, Tigray, in northern Ethiopia, to an Ethiopian father Zenawi Asres from Adwa and Alemash Guebreluel from Adi Quala, Eritrea. He was the third of six children in the family. His first name at birth was “Legesse” (thus Legesse Zenawi, Ge’ez: ለገሰ ዜናዊ legesse zēnāwī). However, he eventually became better known by his nom de guerre Meles, which he adopted in honor of university student and fellow Tigrayan Meles Tekle who was executed by Mengistu’s government in 1975. He received primary education at Queen of Sheba Junior School located in Adwa. It took him 5 years to complete the regular 8 years program as he was smart and was able to skip grades and join the next level. He then joined the prestigious General Wingate High school in Addis Ababa on full scholarship and completed high school in 1972. After high school, Meles studied medicine at Addis Ababa University (at the time known as Haile Selassie University) for two years before dropping out his studies in 1974 to join other students and form Tigrayan National Organization (TNO) the forerunner Tigrayan People’s Liberation Front (TPLF) in Dedebit, Tigray. Aregawi Berhe, a former member of the TPLF, notes that historians John Young and Jenny Hammond “vaguely indicated” Meles as founder TPLF in their books. Aregawi insists that both he and Sibhat Nega joined the Front “months” after it was founded. While a member of the TPLF, Meles establisehed the Marxist-Leninist League of Tigray.

TPLF was one of armed groups struggling Lieutenant Colonel Mengistu Hailemariam and the Derg, the junta which lead Ethiopia under iron fist from 1974-1991. Meles was elected member of the leadership committee in 1979 and chairman of the executive committee of TPLF in 1983. He was the chairperson of both the TPLF and the EPRDF after the EPRDF assumed power at the end of the Ethiopian Civil War in 1991. He was president of the transitional government of Ethiopia (TGE), during which Eritrea seceded from the country and a federal Government that is based on representing the nation and nationality of the country started.

Meles stated that EPRDF’s victory was a triumph for the thousands of TPLF-fighters who were killed, for the millions of Ethiopians who were victims of the country’s biggest famine during the Derg regime, when some estimates put up to 1.5 million deaths of Ethiopians from famine and the Red Terror. Accordingly, he maintained that the big support it received from peasants and rural areas helped EPRDF maintain peace and stability. Foreign support was diverse; the Arab League, as well as Western nations, supported the EPRDF rebels against the communist Moscow-supported government (although the TPLF was at the time Marxist) at the height of the Cold War.

“What the implications of this will be in terms of relations between Ethiopia and the European Union, we will have to wait and see but I don’t think you will be surprised if Ethiopia were to insist that it should not be patronised.”

The United States facilitated peace talks between different rebel groups including EPRDF and the Derg to bring an end to civil war which lasted for 17 years and reach some kind of political settlement in 1991. The talks didn’t bear any fruit as EPRDF’s force were moving to the capital and Mengistu fled the country. The United State agreed to supportthe EPRDF which would have, nevertheless, seize the power without anyone’s support.Many angry demonstrators in Addis Ababa reacted to this by protesting against Herman Cohen, the U.S. State Department’s chief of African affairs who attended a conference that demonstrators viewed as legitimizing the EPRDF. A New York Times editorial commented in 1991,

“Demonstrators cursing the Americans ignore two realities. The cold war is over in Africa, and Ethiopia is no longer a focus of superpower rivalry. Otherwise it would have been unthinkable for four contending Marxist groups to turn to Washington for help. The other reality is that Mr. Cohen cannot undo at the conference table what has happened on the battlefield”

Even though the victory of EPRDF success was welcomed as a relief from DERG’s military rule, there was strong anti-EPRDF sentiments present in many parts of the country and was strongly visible in Addis Ababa. The main opposition to EPDRF’s and by implication Meles’s rule emanated from the fact that EPDRF facilitated and supported at best or didn’t at least oppose the secession of Eritrea which left Ethiopia land-locked. This was just the beginning of the opposition to Meles’ EPRDF party after it gained power and more strong opposition followed. Addis Ababa has since been the center of peaceful opposition to the EPRDF, while the eastern Somali Region has been the most active region for armed opposition.

In July 1991, Convention of Nationalities was held. It was the first Ethiopian multinational convention where delegates of various nations and organizations were given fair and equal representation and observed by various international organizations including the United Nations, Organization for African Unity, European Economic Community, and the United States and the United Kingdom.

In July 2012, questions arose concerning Meles’ health when he did not attend African Union summit meetings in Addis Ababa. Opposition groups claimed that Meles may have already died on 16 July while undergoing treatment in Belgium; however, Deputy Prime Minister Haile Mariam Desalegne attributed Meles’ absence to a minor illness. A press conference, during which the government planned to clarify Meles’ health status, was scheduled for 18 July but postponed until later in the week. While the government acknowledged that Meles had been hospitalised, it stated that his condition was not serious. There were further rumours of his death when he was not seen in public after the 2012 G20 summit[80] and at the time of the death of the head of the Ethiopian Orthodox Church, Abune Paulos.  On 20 August, Meles Zenawi died after contracting an infection in Belgium.