Objective: The current study examines health-related quality of life (HRQOL) and family functioning in a sample of spouse caregivers assisting post-9/11 service members and veterans (SMV) following traumatic brain injury (TBI). Method: Participants were 316 spouse (and partner) caregivers of SMVs following a mild, moderate, severe, or penetrating TBI. Caregivers completed the Family Assessment Device General Functioning subscale, 24 HRQOL questionnaires, and the Mayo-Portland Adaptability Inventory (4th ed.; MPAI-4). The sample was divided into two family functioning groups: Healthy Family Functioning (HFF; n = 162) and Unhealthy Family Functioning (UFF; n = 154). Scores on HRQOL measures that generate T scores using normative data were classified as "clinically elevated," using a cutoff of >60T. Results: Compared with the HFF group, caregivers in the UFF group reported worse scores on all HRQOL measures and worse SMV functional ability on the MPAI-4 Adjustment Index and Anxiety, Depression, and Irritability/Anger/Aggression items (all ps < .001, ds = .41-1.36). A significantly higher proportion of the UFF group had clinically elevated HRQOL scores compared with the HFF group on the majority of measures (Hs = .24-.75). When examining all HRQOL measures simultaneously, the UFF group consistently had a significantly higher cumulative percentage of clinically elevated scores compared with the HFF group (e.g., ≥5 clinically elevated scores: UFF = 53.9% vs. HFF = 22.2%; H = .68). Conclusions: Caring for a SMV following TBI with comorbid mental health problems may have negative implications for their family functioning and the caregiver's HRQOL. Family-centered interventions could be beneficial for military families experiencing distress following SMV TBI and mental health comorbidity. Clinical Impact StatementClose to one in two spouse caregivers assisting service members and veterans (SMVs) following traumatic brain injury reported unhealthy family functioning. Unhealthy family functioning was related to worse caregiver health-related quality of life (HRQOL), whereas healthy family functioning was associated with factors that may mitigate poor HRQOL. Despite increasing evidence of the burden of caregiving, military policy continues to mandate that family services may only be provided in support of the SMV treatment plan. Money spent on caregiver and family-focused programs might improve outcomes for military families and could be achieved at a relatively modest cost with focused goals.