Background: Naloxone is a drug that reverses opioid overdose. Naloxone Access Laws (NALs) increase public access to naloxone and have been considered as one promising solution to reducing opioid-related harm. However, previous studies on whether NALs are effective in reducing opioid overdose mortality found somewhat contradictory results. Our study attempts to provide a more definitive answer to this question by utilizing an approach that matches NAL vs non-NAL states and stratifies by US region and years of implementation. Methods: We assess the causal impact of NALs on state-level opioid-related mortality rate by constructing a comparison group using matching to produce a valid counterfactual scenario, and estimating the effects of NAL using a semi-dynamic staggered difference in differences (DID) model that allows heterogeneous effects across regions and years of implementation. State-level opioid-related mortality data from CDC’s WONDER database and NALs effective from 1999 to 2014 were utilized. Results: We find that NAL effects have reduced fatal opioid-related overdose in western states and have produced minimal or no effects for other regions. Conclusions: The effects of NALs vary across regions and years of implementation. It is important to study the successful experience of the western states.