Key PointsQuestionWhat is the association of sustaining public health interventions with the reduction in opioid-related overdose deaths (OODs) in 4 US states?FindingsIn this decision analytical model that simulated the opioid epidemic in Kentucky, Massachusetts, New York, and Ohio, 4 states highly affected by the opioid epidemic, a 2- to 5-fold increase in initiation and retention of medications for opioid use disorder along with increased supply of naloxone could reduce OODs by an estimated 13% to 17% in Kentucky, 17% to 27% in Massachusetts, 15% to 22% in New York, and 15% to 22% in Ohio after 2 years, compared with the status quo. Sustaining these interventions for 3 additional years could reduce the annual number of OODs at the end of 5 years by 18% to 27% in Kentucky, 28% to 46% in Massachusetts, 22% to 34% in New York, and 25% to 41% in Ohio.MeaningThese findings suggest that sustained implementation of a combination of interventions is critical for achieving a reduction in the annual number of opioid overdose deaths and preventing deaths from increasing again in states highly affected by the opioid epidemic.