BACKGROUND: The lifetime risk of suicide in patients with substance use disorder is five to ten times the risk in the general population. Critically, up to 19% of patients continue to think about and attempt suicide even after accessing treatment. Therefore, suicidality represents a significant clinical concern in patients struggling with substance use that warrants careful investigation of the factors involved. While most previous research has relied on limited cross-sectional designs, a growing number of prospective studies are improving our understanding of the factors involved. However, a systematic study of these factors has not yet been conducted. METHODS: The primary objective of this review and possible meta-analysis will be to identify key risk and protective factors for suicide ideation, attempt, and death in patients accessing substance use treatment, guided by current models of suicide. Secondary and tertiary objectives will be to obtain pooled effect sizes for the factors identified and to disaggregate factors for suicidality before and after treatment, and for suicidal thought versus action. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we will conduct an electronic search of the literature using the databases Embase, Medline, PsycINFO, and Web of Science. Two authors will independently screen studies based on pre-specified inclusion and exclusion criteria, extract relevant data, and assess study quality. Observational and randomized-controlled studies will be included, whereas case-studies and reviews will be excluded. We will extract data on risk and protective factors associated with suicide ideation, attempt (odds or risk ratios), and death (hazard ratio). Given sufficient data (> 5 studies), we will calculate pooled effects using comprehensive meta-analysis. DISCUSSION: This systematic review will contribute to our knowledge of risk and protective factors for suicidality in patients before and after treatment. Understanding these factors will help define areas of research for further investigation to ultimately inform risk assessment and prevention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (reference number: CRD42018076260).