Under the United Nations High Commissioner for Refugees’ (UNHCR) seven-decade mandate, Afghan refugees have faced some of the largest and most protracted experiences with forced displacement. This intergenerational exposure to forced migration has had innumerable consequences for the mental health of this population across different stages of their displacement. Afghan refugees who have resettled into Western nations face a unique set of challenges as they must navigate resettlement into societies that are linguistically, culturally, and spiritually distinct from their own backgrounds. This systematic review explores the (a) effectiveness and (b) cultural adaptation of interventions that have addressed the mental health of Afghan refugees resettled into Western countries since the year 2000. This systematic review will employ the Cultural Treatment Adaptation Framework (CTAF) to organize the extent of cultural adaptations. Through the systematic search of four databases, 1709 studies emerged from our search terms, seven of which met the criteria for this review, for example, study includes more than 2/3 Afghan participants; study includes outcome variables. Studies included programs in Germany, Serbia, Sweden, and Austria. The most common outcomes that interventions addressed included posttraumatic stress disorder (PTSD) (n = 5), depression (n = 3), and quality of life (n = 3). Program modalities ranged between Cognitive Behavioral Therapy (n = 4), emotion regulation (n = 1), family therapy (n = 1), and multimodal interventions (n = 2). Most studies only incorporated peripheral changes to interventions in the service of cultural adaptation, and only one intervention included core changes. This program reported the highest effect sizes in reducing PTSD and depressive symptoms when compared with the rest of the studies. These findings provide a direction for future studies as they consider whether the extent of cultural adaptations can influence the effectiveness of programs for Afghan refugee populations. We provide recommendations for mental health practice with this population, including a special attention to the role of daily stressors, the significance of faith and culture-based meaning making in the service of coping, and the salience of isolation.