The COVID-19 pandemic has tested the capacity for emergency responses in low- and middle- income countries (LMICs), which has highlighted the importance of local public health interventions. Uganda has a robust national response coordination mechanism; however, limited capacities exist at the sub-national level. In 2020, the Uganda Ministry of Health established the Mbale regional emergency operations center (REOC) to coordinate responses to public health and natural disasters in eastern Uganda. The Mbale REOC multidisciplinary regional response team works closely with the Ministry of Health, regional referral hospitals, implementing partners, and academia. We aimed to describe the experience of the Mbale REOC over the 3 years from inception including during the COVID-19 pandemic. 