It is well known that individuals experience difficulties with depressive symptoms and functional status after traumatic brain injury. However, it is unclear what the relationship is between these 2 phenomena and whether there is a biological explanation for. In this secondary analysis, we examined whether depressive symptoms explained postinjury functional status and whether chronic stress and salivary cortisol influenced this relationship. Participants included 75 persons within 24 months of their injury dates who were evaluated or treated in specialty clinics. All participants and a family member or significant other completed survey data, and 50 of the participants provided cortisol data. Results indicated that chronic stress, measured using Cohen's Perceived Stress Scale, completely mediated the relationship between depressive symptoms, measured using the Center for Epidemiological Studies Depression Scale, and psychological functioning, measured using the Patient Competency Rating Scale. Furthermore, those who provided cortisol data displayed hypocortisolemia in their 12-hr profile. Results from this analysis suggest that interventions focused on addressing the chronic stress experience may be important in limiting depressive symptoms and improving psychological functioning. Longitudinal study of this phenomenon is required to understand the progression of chronic stress after traumatic brain injury.