An estimated 109,783 additional people would have died from opioid overdose if the population exposed to opioid overdose risk had remained constant rather than declining; an estimated 260,024 fewer people would have died from overdose if probability of fentanyl involvement in opioid overdose deaths had remained constant rather than increasing. Fentanyl's representation in the U.S. drug supply appears to be a key driver of overdose trends. A declining population exposed to overdose risk over the last decade may be related to prior deaths and to evidence-based efforts to prevent substance use and opioid use disorder.