Background: Evidence-based policymaking is a guiding paradigm of substance use treatment (SUT) policy, that seeks to prioritise scientific criteria over other concerns (e.g., economic, political) when addressing policy decisions. We provide a comprehensive analysis of the context and mechanisms that enable and constrain evidence to improve the Chilean SUT policy and draw some lessons that might be useful to other contexts, particularly low and middle-income countries. Methods: This study relied on an interpretive case study design based on the principles of realist evaluation. We included interviews (N≈17) with international, national, regional, and local policymakers and experts, as well as technical and clinical teams from private and public care SUT providers in Chile. Results: Complex sets of institutional realities and notions of ‘evidence’ shared by actors - between other elements- guide the SUT policy decisions and shape the specific type of evidence considered relevant. Evidence is understood in Chile in narrow terms, and national non-experimental research is often overlooked. This limits the possibility of studying other research questions that could contribute to improving and informing SUT policy. Conclusions: In contexts where addiction research resources are limited, it appears necessary to re-frame the notion of "evidence", to consider relevant national non-experimental knowledge to strengthen SUT policy and achieve its goals. Indeed, this study is an example of how methodological approaches, such as case analysis, can provide a powerful heuristic alternative contribution to the local and global mental health debate.