Background We assessed sociodemographic variables, risky determinants, and type of drug use associated with fatal overdose among people who use drugs (PWUD). Methods Studies in English published from January 1, 1985 to May 1, 2021, were searched on PubMed, Scopus, Cochrane, and Web of Science to identify studies on variables associated with fatal overdoses among PWUDs. After reviewing for study duplicates, the full-text of selected articles were assessed for eligibility using Population, Intervention, Comparator, Outcomes (PICO) criteria: (i) population: PWUD; (ii) intervention: fatal overdose in the past year; (iii) comparator: PWUD who had not fatal overdose; (iv) outcome: fatal overdose in the last year and (v) study type: cross-sectional, cohort, and case-control studies. Results Out of 13,821 articles, 25 studies met eligibility criteria. Our findings showed socio-demographic determinants (younger age, marital status, being homeless, being male,) risky determinants (poor mental health, experience non-fatal overdose and needle sharing), and type of drug use (cocaine disorder, benzodiazepines disorder, alcohol disorder, psychostimulant disorder, polysubstance disorders, and heroin dependence), were significantly associated with fatal overdose among PWUD. Conclusions The present study data indicated that numerous characteristics were correlated with overdose-induced mortality. Such characteristics are certainly interrelated; however, each factor could potentially be targeted for intervention. The most particular reason for death was practicing illicit drug use, including opioids (e.g., heroin).