Abstract Background Youth with epilepsy suffer from stigma, which is closely associated with increased levels of psychological distress, particularly anxiety and depression. Studies have found that the stigma associated with epilepsy is strongly linked to reduced levels of physical activity (PA). However, the combined contribution of stigma and PA to psychological distress remains unclear. Aim This study aims to investigate the mediating role of PA to determine whether PA mediates the relationship between stigma and psychological distress among youth with epilepsy. Methods We conducted a multicentre cross-sectional survey involving youth with epilepsy in nine tertiary hospitals across China from October 2023 to March 2024. The study enrolled 226 youth with epilepsy between the ages of 8 and 18. The dependent variable was psychological distress, assessed using the Depression Anxiety and Stress Scale (DASS-21). Data collection involved the administration of a comprehensive questionnaire that included the DASS-21, the Kilifi Stigma Scale for Epilepsy (KSSE) to assess stigma, and the Physical Activity Rating Scale (PARS-3) to assess PA. Results Psychological distress increased significantly with increasing levels of stigma, whereas a decrease was observed with increasing levels of PA (p