Background: Traumatic brain injury (TBI) remains a significant cause of global mortality and morbidity. This study investigated the association between initial De Ritis ratio (serum AST/ALT) and mortality in moderate-to-severe TBI patients. Methods: This retrospective study analyzed 4415 adult patients with moderate-to-severe TBI (head/neck AIS ≥ 3) from January 2009 to December 2020. Patients were categorized into three groups based on De Ritis ratios: ≤1.2 (n = 1296), 1.2 < ratio ≤ 1.64 (n = 1499), and >1.64 (n = 1620). Propensity score matching was performed to adjust for baseline characteristics including age, sex, comorbidities, Glasgow Coma Scale, and Injury Severity Score. Results: Higher De Ritis ratios were also associated with increased intensive care unit admission rates and longer hospital stays. After propensity score matching, patients with De Ritis ratio > 1.64 showed significantly higher mortality rates compared to the control group (10.3% vs. 7.9%, odds ratio (OR) = 1.33, 95% confidence interval (CI) 1.01–1.77, p = 0.046). No significant mortality difference was found between patients with De Ritis ratio ≤1.2 and the control group. Conclusions: Initial De Ritis ratio>1.64 serves as an independent predictor of mortality in moderate-to-severe TBI patients. This readily available laboratory parameter could provide valuable prognostic information for early risk stratification in TBI management.