, Georgios Nikolaou
(1) Background: Mental health disparities persist across culturally diverse populations despite robust cognitive–behavioral therapy (CBT) efficacy evidence. Cultural neuroscience suggests that neurobiological processes underlying therapeutic mechanisms may exhibit culturally variable patterns, yet integration of neuroscientific frameworks into culturally adapted interventions remains limited. (2) Methods: Following PRISMA 2020 guidelines, we systematically searched PubMed/MEDLINE, PsycINFO, Scopus, and Web of Science (January 2014–December 2024) for peer-reviewed studies examining CBT interventions targeting depression, anxiety, PTSD, or psychological distress in culturally diverse populations. Ninety-four studies were synthesized using narrative methods; methodological heterogeneity precluded meta-analytic pooling. (3) Results: Culturally adapted CBT interventions consistently demonstrated superior outcomes compared to standard protocols across diverse populations. Group formats showed exceptional retention in collectivistic cultures, while hybrid technology-enhanced models achieved strong completion rates across contexts. Cultural adaptation enhanced engagement (e.g., 84% vs. 52% retention in refugee populations) and maintenance of treatment gains. Individual studies reported effect sizes ranging from d = 0.29 to d = 2.4; substantial within-group variability was observed, and identified patterns likely reflect learned cultural adaptations rather than inherent biological differences. Direct neuroimaging evidence within included studies remained limited (13.8%). (4) Conclusions: The evidence supports culturally adapted interventions as essential for equitable mental health outcomes. Cultural experiences may influence therapeutic processes, suggesting potential benefit from considering culturally variable processing patterns alongside universal mechanisms. However, conclusions regarding specific neural pathways remain preliminary, and individual assessment remains paramount, with cultural background representing one factor among many in treatment planning.