This exploratory study examined the impact of health literacy on quality of life (QoL) in patients with treatment-resistant epilepsy (TRE). Health literacy is a discrete form of literacy in which an individual can readily interpret prose and apply that skill to understand medical, pharmaceutical, and self-management information. From the perspectives of cultural health capital (CHC) and social disability theory, we hypothesized that greater levels of health literacy would be associated with a higher QoL score. The sample (n = 79) included adult patients with TRE enrolled in the University of Alabama at Birmingham Cannabidiol Program. The data were analyzed by using nested linear regression. Respondents aged 19–63 years (mean, standard deviation [SD] = 32.9 [13.65]) and were 92% white; 44% of patients were in Special Education until age 21 years, and 29% reported a total annual family income of less than $25,000. Significant bivariate relationships were found between health literacy and QoL (p =.004), age (p =.0001), and income (p =.036). There was a significant difference in health literacy scores for patients who completed high school or less (mean [SD] = 0.68 [0.86]) and those with any postsecondary education (mean [SD] = 1.59 [1.0]). The regression results showed health literacy to be positively associated with QoL where a 1% increase in health literacy was associated with a 6.61-point increase in QoL (p =.004), and this pattern persisted through each addition of other independent factors and control variables. This is one of the first studies investigating the role of health literacy in QoL among patients with TRE. The results suggest that health literacy is important and may function as a tool through which healthcare participation is expanded. Further research is needed with larger, more diverse, and longitudinal samples to accurately model the development of health literacy and its impact on QoL in this population.