After leaving university in 1966, Afwerki served as deputy division commander in the ELF (1967–70). In 1970, he and his group founded the EPLF, which later became the dominant power in the history of the country. Until 1977, he held various leadership positions and in 1987, the Front, in its Second Congress elected him as the organization's Secretary General.
During the civil war, Afwerki chose not to base himself and his leadership in Europe or North America. Instead, he remained within Eritrea (often at the stronghold of Naqfa) organizing guerilla warfare against the Ethiopian government troops. Overseas, his supporters waged an extremely effective campaign of political persuasion, winning international support, if not official recognition.
The EPLF has played a critical role throughout Eritrea's independence struggle. In 1988, the EPLF was able to force the Ethiopian army to withdraw its forces from Keren, Eritrea's second largest city, and several western lowlands. Under his leadership, the EPLF won the war with Ethiopia in May 1991, and Eritrea gained independence. The government that took power in Ethiopia in May 1991 declared itself amenable to an independent Eritrea and agreed to cooperate with the Provisional Government of Eritrea (PGE) over access to the port of Assab.