© 2020 Coronavirus disease 2019 (COVID-19) will have a lasting impact on public health. In addition to the direct effects of COVID-19 infection, physical distancing and quarantine interventions have indirect effects on health. While necessary, physical distancing interventions to control the spread of COVID-19 could have multiple impacts on people living with opioid use disorder, including impacts on mental health that lead to greater substance use, the availability of drug supply, the ways that people use drugs, treatment-seeking behaviors, and retention in care. The degree to which COVID-19 will impact the opioid epidemic and through which of the possible mechanisms that we discuss is important to monitor. We employed simulation modeling to demonstrate the potential impact of physical distancing on overdose mortality.