Introduction: On March 13, 2020, the U.S. declared COVID-19 to be a national emergency. As communities adopted mitigation strategies, there were potential changes in the trends of injuries treated in emergency department. This study provides national estimates of injury-related emergency department visits in the U.S. before and during the pandemic. Methods: A secondary retrospective cohort study was conducted using trained, on-site hospital coders collecting data for injury-related emergency department cases from medical records from a nationally representative sample of 66 U.S. hospital emergency departments. Injury emergency department visit estimates in the year before the pandemic (January 1, 2019-December 31, 2019) were compared with estimates of the year of pandemic declaration (January 1, 2020-December 31, 2020) for overall nonfatal injury-related emergency department visits, motor vehicle, falls-related, self-harm-, assault-related, and poisoning-related emergency department visits. Results: There was an estimated 1.7 million (25%) decrease in nonfatal injury-related emergency department visits during April through June 2020 compared with those of the same timeframe in 2019. Similar decreases were observed for emergency department visits because of motor vehicle-related injuries (199,329; 23.3%) and falls-related injuries (497,971; 25.1%). Monthly 2020 estimates remained relatively in line with 2019 estimates for self-harm-, assault-, and poisoning-related emergency department visits. Conclusions: These findings provide updates for clinical and public health practitioners on the changing profile of injury-related emergency department visits during the COVID-19 pandemic. Understanding the short- and long-term impacts of the pandemic is important to preventing future injuries. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.