Background <p>Over 100 overdose prevention sites (OPS) operate in various jurisdictions, including Australia, Canada, the United States, and several European countries. However, despite the increasing prevalence of people who use illegal drugs, including those who inject drugs, no such facility currently operates in Africa, Asia, the Middle East, the Caribbean, or Central and South America. Except for Canada and a few sites in the US, no sanctioned facility currently operates in Mexico.</p> Methods <p>This systematic review will identify peer-reviewed studies, reports, and theses that evaluate the cost and benefits of OPS, relying on five electronic databases (ECONLIT, Google Scholar, Medline, PubMed, and Web of Science). A search strategy based on the PRESS approach will guide the initial search for articles. Based on the PRISMA, community researchers will screen titles and abstracts using the specified inclusion criteria in EndNote X20, and the results will be uploaded into Covidence. Community reviewers using Covidence will examine the complete text, including the title and abstract. All articles reported through the initial search will be further screened based on Cheers and Drummond criteria to identify weaknesses in the research while extracting additional information and data related to costs, benefits, programs, or services. The final data analysis will include the range of cumulative benefits, costs, and ratios associated with operating OPS.</p> Discussion <p>This review has the potential to provide evidence-based knowledge through a community-based research approach on the cost savings of public health interventions implemented through harm reduction philosophy for underserved populations.</p>