Compared to the general population or to other groups of people with chronic health conditions, individuals with epilepsy are more likely to also experience internalizing disorders (i.e., depression and/or anxiety) during their lifetime. In adults, these comorbid conditions are thought to be indexed by specific neural biomarkers, including irregularities in the structure and function of frontal and temporal regions of the brain. However, less work has investigated whether similar patterns may be noted in children and adolescents with epilepsy, who are at risk of developing depression and/or anxiety. The current study capitalized on the fact that youth with epilepsy often undergo MRI (magnetic resonance imaging) scans, PET (positron emission tomography) scans, and psychological assessments as part of their clinical evaluations. We examined whether youth with epilepsy who experienced clinically-significant levels of internalizing problems had different patterns of brain structure and/or function than youth who scored in the normal range for such symptoms. We found that 42% of youth in our sample scored in the clinical range for internalizing symptoms on a parent-report of psychological well-being (Child Behavior Checklist; Achenbach, 2001)—suggesting that anxiety and depression may be a common concern for many young patients. Symptoms were not predicted by characteristics of the illness (like age of seizure onset or location of seizure focus) nor of the patient (like age or gender). However, youth in the clinical range showed reduced cortical volume overall, as well as cortical thinning and decreased function (measured via glucose reuptake) in bilateral parietal/occipital lobes and left temporal regions, compared to youth in the normal range. A follow-up classifier analysis demonstrated that these brain characteristics were predictive of internalizing problems at an individual level. Taken together, our findings suggest that children and adolescents with epilepsy who show widespread reductions in cortical thickness and neural function in clinical evaluations may benefit from intensified psychological evaluation and support for possible mood and anxiety symptoms.