ObjectivesTo describe the association between population size, population growth and opioid overdose deaths—overall and by type of opioid—in US commuting zones (CZs) in three periods between 2005 and 2017.Settings741 CZs covering the entirety of the US CZs are aggregations of counties based on commuting patterns that reflect local economies.ParticipantsWe used mortality data at the county level from 2005 to 2017 from the National Center for Health Statistics.OutcomeOpioid overdose deaths were defined using underlying and contributory causes of death codes from the International Classification of Diseases, 10th revision (ICD-10). We used the underlying cause of death to identify all drug poisoning deaths. Contributory cause of death was used to classify opioid overdose deaths according to the three major types of opioid, that is, prescription opioids, heroin and synthetic opioids other than methadone.ResultsOpioid overdose deaths were disproportionally higher in largely populated CZs. A CZ with 1.0% larger population had 1.10%, 1.10%, and 1.16% higher opioid death count in 2005–2009, 2010–2014, and 2015–2017, respectively. This pattern was largely driven by a high number of deaths involving heroin and synthetic opioids, particularly in 2015–2017. Population growth over time was associated with lower age-adjusted opioid overdose mortality rate: a 1.0% increase in population over time was associated with 1.4% (95% CI: −2.8% to 0.1%), 4.5% (95% CI: −5.8% to −3.2%), and 1.2% (95% CI: −4.2% to 1.8%) lower opioid overdose mortality in 2005–2009, 2010–2014, and 2015–2017, respectively. The association between positive population growth and lower opioid mortality rates was stronger in larger CZs.ConclusionsOpioid overdose mortality in the USA was disproportionately higher in mid-sized and large CZs, particularly those affected by declines in population over time, regardless of the region where they are located.