OBJECTIVE: To present an evidence-based review of randomized controlled trials (RCTs) evaluating interventions for mental health post-moderate to severe traumatic brain injury (post-MSTBI), as part of an extensive database that has been conceptualized as a living systematic review. METHODS: Systematic searches were conducted for RCTs published in the English language in MEDLINE, PubMed, Scopus, CINAHL, EMBASE, and PsycINFO, up to and including December 2022, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodological quality of RCTs was assessed using the Physiotherapy Evidence Database scale, and the level of evidence was assigned using a modified Sackett scale. RESULTS: Eighty-seven RCTs examining mental health interventions and outcome measures post-MSTBI were included. These studies collectively enrolled 6471 participants. A total of 41 RCTs (47.1%) were conducted in the United States and 56 studies (64.4%) were published after 2010. A total of 62 RCTs (71.3%) examined nonpharmacological interventions and 25 RCTs (28.7%) examined pharmacological interventions. Effective pharmacological treatments included desipramine and cerebrolysin; methylphenidate and rivastigmine showed conflicting evidence. Cognitive behavioral therapy (CBT) was found to be effective for hopelessness, stress, and anxiety, compared to usual care; however, it may be as effective as supportive psychotherapy for depression. CBT combined with motivational interviewing may be as effective as CBT combined with nondirective counseling for depression, stress, and anxiety. Acceptance and commitment therapy was effective for anxiety, stress, and depression. Tai Chi, dance, and walking appeared to be effective for depression and stress, while other nonpharmacological treatments such as peer mentoring showed limited effectiveness. CONCLUSION: This evidence-based review provides a comprehensive overview of the research landscape of RCTs addressing mental health post-MSTBI. The findings from these RCTs may be valuable for health care professionals, researchers, and policymakers involved in the field of mental health and neurorehabilitation.