Traumatic brain injuries (TBI) and mental health or substance use disorders (MHSU) are global public health concerns due to their prevalence and impact on individuals and societies. However, care for individuals with TBI and MHSU remains fragmented with a lack of appropriate services and supports across the continuum of healthcare. This systematic review provided an evidence-based foundation to inform opportunities to mobilize and adapt existing resources to integrate care for individuals with TBI and MHSU by comprehensively summarizing existing integrated activities and reported barriers and facilitators to care integration. MEDLINE, EMBASE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, Sociological Abstracts, and Dissertations & Theses Global were independently reviewed by two reviewers based on pre-determined eligibility criteria. Data on the integration activity, level and type of integration, reported barriers and facilitators, and the strategies aligning with the World Health Organization's (WHO) Framework on Integrated Person-Centred Care were extracted to form the basis for a narrative synthesis. Fifty-nine peer-reviewed articles were included, describing treatments (N = 49), programs (N = 4), or screening activities (N = 7). Studies discussing clinical integration at the micro- (N = 38) and meso- (N = 10) levels, service integration at the micro- (N = 6) and meso- (N = 5) levels, and functional integration at the meso-level (N = 1) were identified. A minority of articles reported on facilitators (e.g., cognitive accommodations in treatment plans; N = 7), barriers (e.g., lack of education on cognitive challenges associated with TBI; N = 2), or both (N = 6), related to integrating care. This review demonstrated that integrated TBI and MHSU care already exists across a range of levels and types. Given the finite and competing demands for healthcare resources, cognitive accommodations across treatment plans to facilitate integrated TBI and MHSU care should be considered. Multidisciplinary teams should also be explored to provide opportunities for education among health professionals so they can be familiar with TBI and MHSU. Trial registration: Prospero Registration: CRD42018108343.