Seyoum was the Ethiopian minister of foreign affairs for nearly 20 years, from 1991 until he was replaced after the 2010 parliamentary election. He was also an executive member of the Central Committee of the EPRDF. He was influential in the Eritrean Ethiopian war and on 18 June 2000, Seyoum Mesfin, and his Eritrean counterpart, Haile Woldetensae, signed a peace agreement ending the war. On 28 December 2004, Mesfin made a speech to the UN General Assembly in New York on the policy in the region, in particular the relationship of Ethiopia to Eritrea and Somalia. In 2007, Seyoum indicated that Eritrea had breached the agreements that ended its war and Ethiopia might end all or part of those agreements. He was also a member of the House of Peoples' Representatives, representing Adigrat.