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The rural and northern communities of British Columbia (BC) have their own barriers to accessing mental health and substance use services that lead to greater susceptibility to psychological disorders and substance abuse. Although there is increasing awareness about these inequalities, the research on mental health and substance use outcomes in these groups is still piecemeal. The proposed systematic review provided a synthesis of the current literature on mental health and substance use outcomes in rural and northern BC, the population-specific risk and protective factors, and the effectiveness of planned interventions to address the identified issues. Quantitative studies published in peer-reviewed journals, mixed-methods studies, and government and other health reports published in English were also considered. Predefined terms were used to search databases such as PubMed, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Web of Science, as well as grey literature sources, for mental health, substance use, rurality, and BC. Two independent reviewers performed title/abstract and full-text screening, and any discrepancies were settled by consensus. A standardized form was used to extract data, focusing on the characteristics of the studies, prevalence, and types of mental health and substance use outcomes, risk and protective factors, and intervention outcomes. Quality checking was conducted using the Newcastle-Ottawa Scale for observational studies, the Critical Appraisal Skills Programme (CASP) Qualitative Studies Checklist for the qualitative studies, and the National Institutes of Health (NIH) Quality Assessment Tool for before-after (pre-post) studies with no control group. Primary evidence suggests that depression, anxiety, and substance use disorders are higher in rural and northern BC due to the lack of socioeconomic and service access and geographic isolation. The available evidence of interventions is disparate and insufficient, and suggests gaps in specific mental health and substance use interventions. The combination of these results can be a basis for policy formulation and distribution of resources, as well as culturally sensitive interventions to decrease mental health and substance use disparities within underserved BC groups.