Opioid overdose deaths remain a major public health crisis. We used a system dynamics simulation model of the U.S. opioid-using population age 12 and older to explore the impacts of 11 strategies on the prevalence of opioid use disorder (OUD) and fatal opioid overdoses from 2022 to 2032. These strategies spanned opioid misuse and OUD prevention, buprenorphine capacity, recovery support, and overdose harm reduction. By 2032, three strategies saved the most lives: (i) reducing the risk of opioid overdose involving fentanyl use, which may be achieved through fentanyl-focused harm reduction services; (ii) increasing naloxone distribution to people who use opioids; and (iii) recovery support for people in remission, which reduced deaths by reducing OUD. Increasing buprenorphine providers’ capacity to treat more people decreased fatal overdose, but only in the short term. Our analysis provides insight into the kinds of multifaceted approaches needed to save lives.