IntroductionDramatic increases in U.S. drug overdose deaths involving synthetic opioids, especially fentanyl, beginning around 2014 have driven a marked progression in overall drug overdose deaths in the U.S., which sharply rose to unprecedented levels amid the COVID-19 pandemic. Disparities in drug overdose deaths by educational attainment (EA) during the fentanyl era of the drug overdose epidemic and its intersection with the COVID-19 pandemic have not been widely scrutinized. MethodsUtilizing restricted-use mortality data from the National Vital Statistics System and population estimates from the American Community Survey, we estimated annual national age-adjusted mortality rates (AAMRs) from drug overdoses jointly stratified by EA and sex for adults aged 25–64 from 2015 to 2021. State-level AAMRs in 2015 and 2021 were also estimated to examine the geographic variation in the cumulative evolution of EA-related disparities over the course of the analysis period. ResultsNationally, AAMRs rose fastest among persons with at most a high school-level education, whereas little to no change was observed for bachelor’s degree holders, widening pre-existing disparities. During the analysis period, the difference in national AAMRs between persons with at most a high school-level education and bachelor’s degree holders increased from less than 8-fold (2015) to approximately 13-fold (2021). The national widening of EA-related disparities accelerated amid the COVID-19 pandemic, and they widened in nearly every state. Among non-bachelor’s degree holders, national AAMRs increased markedly faster for males. ConclusionsThe widening disparities in drug overdose deaths by EA are a likely indicator of a rapidly increasing socioeconomic divide in drug overdose mortality more broadly. Policy strategies should address upstream socioeconomic drivers of drug use and overdose, particularly among males.