She began her career in the Ministry of Education and later joined the Ministry of Foreign Affairs in 1988. She began her long diplomatic carrier as Ambassador to Senegal with accreditation to Mali, Guinea, Guinea-Bissau, Cape Verde, and the Gambia. She served as Ambassador in Djibouti and as Permanent Representative to the Inter-Governmental Authority on Development (IGAD) for 10 years.

She was subsequently appointed as Ambassador of Ethiopia to France, Tunisia and Morocco and Permanent Representative to UNESCO. After her return to Ethiopia she was appointed Permanent Representative to the African Union and Director General for African Affairs at the Ministry of Foreign Affairs of Ethiopia. 

President Sahle-Work Zewde joined the United Nations in 2009 and served as Special Representative of the United Nations Secretary-General (SRSG) and Head of the United Nations Integrated Peace-building Office in the Central African Republic (BINUCA) thus becoming the first African woman to become an SRSG.  

In 2011, she was appointed as the first dedicated Director-General of the United Nations Office in Nairobi (UNON) at the level of Under-Secretary-General. In June 2018, she was appointed by Secretary- General Antonio Guterres as his Special Representative to the African Union and Head of the United Nations Office to the African Union (UNOAU). She was the first woman to hold these two positions.