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People with serious head injuries describe psychological distress and existential disruptions, often struggling to find meaning in their lives post-injury. Understanding the differential associations of the three facets of the tripartite model of meaning - coherence, purpose, and mattering - among people with serious head injury may thus benefit and guide intervention and treatment. Using data from the Midlife in the United States national survey, we assessed differences in coherence, purpose, and mattering between people with serious head injury and case matched controls. Differences in depression were also assessed, as was whether meaning mediated the relationship between group and depression. Independent samples t-tests found that people with serious head injury reported less coherence and greater depression than controls, but no differences were found for purpose or mattering. Coherence further mediated the relationship between group and depression. These findings suggest that targeting coherence may support clinical interventions and improve patient health and well-being.