Cannabidiol (CBD) trials offer an opportunity to examine social factors that shape outcomes of patients with treatment-resistant epilepsy. Prior research of patients treated with CBD for epilepsy describes financial struggles of these patients/families and the association between socioeconomic status and patient-centered outcomes. However, social determinants of health in this population are still poorly understood, mainly due to data scarcity. This study aimed to establish feasibility of assessing social stress, social support, and religious participation and their associations with outcomes (perceived health, quality of life, and mood) in patients treated with CBD for epilepsy. Data were collected during 2015–2018 through structured face-to face interviews with patients/caregivers in a CBD compassionate access/research program in the southern United States. Adult (ages 19–63; n = 65) and pediatric (ages 8–19; n = 46) patients or their caregivers were interviewed at the time of enrollment in the study. Social stress was assessed with stressful life events, perceived stress, epilepsy-related discrimination, and economic stressors; social support with the Interpersonal Support Evaluation List [ISEL]-12; and religious participation with frequency of religious attendance. The results showed economic stressors to be associated with poor overall health, but no associations were noted between stress, support, and religious participation measures and quality of life or mood. Despite a robust data collection plan, completeness of the data was mixed. We discuss lessons learned and directions for future research and identify potential refinements to social data collection in people with treatment-resistant epilepsy during clinical trials.