Study objective: People with opioid use disorder are vulnerable to disruptions in access to addiction treatment and social support during the COVID-19 pandemic. Our study objective was to understand changes in emergency department (ED) utilization following a nonfatal opioid overdose during COVID-19 compared to historical controls in 6 healthcare systems across the United States. Methods: Opioid overdoses were retrospectively identified among adult visits to 25 EDs in Alabama, Colorado, Connecticut, North Carolina, Massachusetts, and Rhode Island from January 2018 to December 2020. Overdose visit counts and rates per 100 all-cause ED visits during the COVID-19 pandemic were compared with the levels predicted based on 2018 and 2019 visits using graphical analysis and an epidemiologic outbreak detection cumulative sum algorithm. Results: Overdose visit counts increased by 10.5% (n=3486; 95% confidence interval [CI] 4.18% to 17.0%) in 2020 compared with the counts in 2018 and 2019 (n=3020 and n=3285, respectively), despite a 14% decline in all-cause ED visits. Opioid overdose rates increased by 28.5% (95% CI 23.3% to 34.0%) from 0.25 per 100 ED visits in 2018 to 2019 to 0.32 per 100 ED visits in 2020. Although all 6 studied health care systems experienced overdose ED visit rates more than the 95th percentile prediction in 6 or more weeks of 2020 (compared with 2.6 weeks as expected by chance), 2 health care systems experienced sustained outbreaks during the COVID-19 pandemic. Conclusion: Despite decreases in ED visits for other medical emergencies, the numbers and rates of opioid overdose-related ED visits in 6 health care systems increased during 2020, suggesting a widespread increase in opioid-related complications during the COVID-19 pandemic. Expanded community- and hospital-based interventions are needed to support people with opioid use disorder and save lives during the COVID-19 pandemic.