The present study examined the mediators of change accounting for outcomes of a previously published study on acceptance and commitment therapy for the self-management of epilepsy and its life restricting impact. Conducted with 27 poor South Africans, a 9-h ACT protocol that included seizure management methods was shown to greatly reduce epileptic seizures and to increase quality of life over the next year as compared to an attention placebo control. A series of bootstrapped non-parametric multiple mediator tests showed that pre to follow-up changes in: seizures, quality of life, and well-being outcomes were mediated to a degree by ACT process measures of epilepsy-related acceptance or defusion, values attainment, persistence in the face of barriers, or their combination. The results of this study contribute to the understanding of the contextual conditioning mechanisms at work for those suffering from epilepsy and may show that helping people live vital lives may also help to reduce seizures.