Objectives. To identify promising practices for implementing COVID-19 vaccination sites. Methods. The Centers for Disease Control and Prevention (CDC) and Federal Emergency Management Agency (FEMA) assessed high-throughput COVID-19 vaccination sites across the United States, including Puerto Rico, after COVID-19 vaccinations began. Site assessors conducted site observations and interviews with site staff. Qualitative data were compiled and thematically analyzed. Results. CDC and FEMA conducted 134 assessments of high-throughput vaccination sites in 25 states and Puerto Rico from February 12 to May 28, 2021. Promising practices were identified across facility, clinical, and cross-cutting operational areas and related to 6 main themes: addressing health equity, leveraging partnerships, optimizing site design and flow, communicating through visual cues, using quick response codes, and prioritizing risk management and quality control. Conclusions. These practices might help planning and implementation of future vaccination operations for COVID-19, influenza, and other vaccine-preventable diseases. Public Health Implications. These practices can be considered by vaccination planners and providers to strengthen their vaccination site plans and implementation of future high-throughput vaccination sites. (Am J Public Health. 2023;113(8):909-918. https://doi.org/10.2105/AJPH.2023.307331).