In 2016-2017, the H5N8 strain of highly pathogenic avian influenza (HPAI) spread worldwide and Uganda reported the first occurrence of the disease in its poultry and wild birds. Genetic analysis revealed that the virus clusters with 2.3.4.4 group B strains from birds in central and southern Asia, and thus forms part of the 2.3.4.4 group B clade. Since Uganda is in the path of two major migratory bird flyways, it is likely that infected migratory wild birds played a crucial role in the introduction of H5N8 HPAI viruses into Uganda. The outbreaks happened in the districts of Wakiso, Masaka and Kalangala and affected domestic and wild birds. A One Health Multisectoral Coordination Committee, consisting of a National Task Force, Technical Working Groups and District Disaster Management Committees, was immediately activated to coordinate the preparedness and response efforts to control the disease. In all the affected districts, surveillance was intensified on both domestic and wild birds; biosecurity measures were increased; and movement controls, culling, cleaning, disinfection and safe disposal of carcasses were implemented. Awareness of the disease was raised through education materials, leaflets and brochures distributed to farmers. Finally, Uganda successfully controlled the H5N8 outbreak, using its national preparedness and response mechanisms and through collaboration with international partners. The emergence and spread of this virus strain in Uganda and other parts of Africa poses a significant threat to the poultry industry and food security.