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.