Objective: To examine the role of psychological flexibility as a potential mediator in the relationship between involvement in a guided self-help intervention, Self-Help Plus, and psychological distress in a sample of South Sudanese refugee women living in northern Uganda. Method: We conducted secondary analysis of data from a cluster randomized controlled trial conducted in 2018. We used multilevel mediation modeling to explore the relationship of psychological flexibility, as measured by the Acceptance and Action Questionnaire (AAQ-II), as a mediating factor in the relationship between Self-Help Plus involvement and general psychological distress as measured by the Kessler Psychological Distress Scale–6 (K6). Results: We found strong multilevel mediation of decreased K6 scores in the treatment group by AAQ-II scores (multilevel b = −3.28). A more pronounced mediation effect was discovered immediately post intervention (b = −1.09) compared to 3-month follow-up (b = −0.84). This is in line with the current literature that demonstrates the role of psychological flexibility as a primary mechanism of change in ACT-based interventions. Conclusions: Psychological flexibility is a contributing component in the theory of change for this ACT-based intervention. Identifying the core components of interventions allows for more effective adaptation and implementation of relevant services, especially in low-resource contexts. What is the public health significance of this article?: Public mental health in humanitarian settings demands interventions with flexibility in implementation, options for paraprofessional use, and low-resource demand. Accordingly, the purpose of this investigation is to contextualize a promising, low-intensity ACT-based intervention within existing literature and expand on its primary mechanism of change, increases in psychological flexibility. This article suggests that specific elements of this therapy are readily adapted for use in novel cultural settings and facilitate change in psychological flexibility while retaining the key components of an effective intervention. [ABSTRACT FROM AUTHOR]