The Commission on Combating Synthetic Opioid Trafficking, established under Section 7221 of the National Defense Authorization Act for Fiscal Year 2020, was charged with examining aspects of the synthetic opioid threat to the United States—specifically, with developing a consensus on a strategic approach to combating the illegal flow of synthetic opioids into the United States. This final report describes items involving the illegal manufacturing and trafficking of synthetic opioids, as well as the deficiencies in countering their production and distribution, and includes action items directed to appropriate executive branch agencies and congressional committees and leadership.