The coronavirus disease 2019 (COVID-19) global response underscores the need for a multidisciplinary approach that integrates and coordinates various public health systems-surveillance, laboratory, and health-care systems/networks, among others-as part of a larger emergency response system. Multidisciplinary public health rapid response teams (RRTs) are one mechanism used within a larger COVID-19 outbreak response strategy. As COVID-19 RRTs are deployed, countries are facing operational challenges in optimizing their RRT's impact, while ensuring the safety of their RRT responders. From March to May 2020, United States Centers for Disease Control and Prevention received requests from 12 countries for technical assistance related to COVID-19 RRTs and emergency operations support. Challenges included: (1) an insufficient number of RRT responders available for COVID-19 deployments; (2) limited capacity to monitor RRT responders' health, safety, and resiliency; (3) difficulty converting critical in-person RRT operational processes to remote information technology platforms; and (4) stigmatization of RRT responders hindering COVID-19 interventions. Although geographically and socioeconomically diverse, these 12 countries experienced similar RRT operational challenges, indicating potential applicability to other countries. As the response has highlighted the critical need for immediate and effective implementation measures, addressing these challenges is essential to ensuring an impactful and sustainable COVID-19 response strategy globally.