Abstract Mandatory prescription drug monitoring programs and cannabis legalization have been hypothesized to reduce overdose deaths. We examined associations between prescription monitoring programs with access mandates (must-query PDMPs), legalization of medical and recreational cannabis supply, and opioid overdose deaths in United States counties in 2013-2020. Using data on overdose deaths from the National Vital Statistics System, we fit Bayesian spatiotemporal models to estimate risk differences and 95% credible intervals (CrIs) in county-level opioid overdose deaths associated with enactment of these state policies. Must-query PDMPs were independently associated with on average 0.8 (95% CrI, 0.5-1.0) additional opioid-involved overdose deaths per 100 000 person-years. Legal cannabis supply was not independently associated with opioid overdose deaths in this time period. Must-query PDMPs enacted in the presence of legal (medical or recreational) cannabis supply were associated with 0.7 (95% CrI, 0.4-0.9) more opioid-involved deaths relative to must-query PDMPs without any legal cannabis supply. In a time when overdoses are driven mostly by nonprescribed opioids, stricter opioid prescribing policies and more expansive cannabis legalization were not associated with reduced overdose death rates. This article is part of a Special Collection on Mental Health.