Objective: Caring for a child with epilepsy poses various psychological, physical and medical challenges; these can lead to caregiver burden. The aim of this study was to identify predictors of burden with mothers caring for a child with epilepsy. Our analyses included sociodemographic (e.g., ethnicity), mental health (e.g., symptoms of anxiety, depression) and physiological factors (e.g., extent of pharmacotherapy). Methods: A total of 168 mothers caring for a child with epilepsy were recruited while attending the Pediatric Neurology Clinic at Soroka Medical Center, Be’er Sheva, Israel. This cross-sectional sample included 130 Jewish-Israeli and 38 Arab-Bedouin mothers who completed parallel questionnaire batteries that included the Zarit Burden Interview and other scales translated and validated in Hebrew and Arabic. We computed path analyses to identify both direct and indirect predictors of caregiver burden. Results: Burden was directly predicted by emotional exhaustion, symptoms of anxiety and (Bedouin) ethnicity. Indirect effects on burden included illness severity (via emotional exhaustion), ethnicity and emotional exhaustion (both via anxiety). That is, both ethnicity and emotional exhaustion directly and indirectly predicted caregiver burden via greater anxiety. Illness severity indirectly predicted symptoms of depression, anxiety and caregiver burden. We found that 55% of epilepsy care burden was predicted by this path model. Conclusions: Bedouin mothers reported greater illness severity, symptoms of depression, anxiety and caregiver burden. Differences between groups in epilepsy severity suggest that less severe cases in the Bedouin community do not come to clinical attention (e.g., are concealed due to stigma). These findings underscore the need for health promotion strategies and interventions for caregivers tailored to account for ethnic and cultural differences.