Although seizure control is a critical goal for persons with epilepsy (PWE) from the biomedical perspective, there is growing support for approaches that take into account the effect of epilepsy on the whole person (the biopsychosocial perspective). We hypothesized that PWE who report normal activity limitations due to epilepsy and poor social/emotional support would report poor mental health regardless of whether they report having seizures in the past 3 months or currently taking medication for their epilepsy. In 2005 and 2006, twenty-two states asked about epilepsy in the Behavioral Risk Factor Surveillance System (BRFSS). A set of survey weight-adjusted logistic regression analyses were conducted to examine self-reported poor mental health. Our findings reveal that both normal activity limitations due to epilepsy and poor social/emotional support are significant predictors of reporting poor mental health. After controlling for social support, demographics, comorbidities, and health behaviors we determined that those reporting normal activity limitations due to epilepsy are more likely to report poor mental health (odds ratio [OR] 3.05, 95% confidence interval [CI] 1.41–6.58). Similarly, after controlling for the same factors, PWE with poor social/emotional support are more likely to report poor mental health (OR 3.22, 95% CI 1.84–5.61). In contrast, reported seizures in the past 3 months (OR 1.12, 95% CI 0.56–2.25) or current use of medication (OR 0.58, 95% CI 0.30–1.10) were not significantly associated with poor mental health. These population-based findings support the need for clinical approaches that address psychosocial issues in addition to seizure control and treatment.