Research has documented the deleterious effects on caregivers of providing care for an individual with traumatic brain injury (TBI). TBI caregivers in Mexico specifically have reduced health-related quality of life (HRQOL) across both physical and mental health domains. The purpose of the current study was to uncover the system of connections between Mexican TBI caregivers' HRQOL and their mental health. A cross-sectional survey was conducted at a public medical facility in Guadalajara, México. Ninety family caregivers of individuals with TBI completed measures of HRQOL, satisfaction with life, depression, and burden. A canonical correlation analysis revealed that the better the caregivers' HRQOL, the better their mental health was, with the effect reaching a large-sized effect. A distinct pattern emerged linking caregivers' higher energy levels and better social functioning to lower depression and greater satisfaction with life. A series of multiple regressions similarly uncovered that the most robust independent HRQOL predictors of caregiver mental health were vitality and social functioning. Especially for TBI caregivers with poor health, behavioral health interventions in Latin America that target the HRQOL domains of social functioning and vitality may significantly improve caregiver mental health, and as a result, informal care for TBI.