Traumatic brain injury (TBI) is a significant health problem with a high mortality rate. Inflammatory markers can predict the prognosis of TBI where neuroinflammation is essential. In this study, the prognostic value of the systemic immune-inflammation index (SII), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) at admission in patients with critical TBI was investigated. Patients with moderately severe TBI in the intensive care unit (ICU) of a tertiary center between June 2020 and June 2022 were retrospectively reviewed. Patients were classified into survivor and mortality groups. The predictive performance of SII, PLR, and NLR levels calculated from blood results at admission and 28-day mortality and patient outcomes were analyzed. One hundred sixty-one patients were included in this study. The median age of the entire population was 41 (18–90) years, and 80.7% (n = 130) of the patients were male. Falls (42.2%) and traffic accidents (40.4%) were the most common causes of TBI. The most common primary diagnoses in patients with TBI were acute subdural hematoma (30.4%) and subarachnoid hemorrhage (26.1%). The SII and NLR levels were significantly higher in the mortality group, and PLR levels were significantly lower (P = .004, P < .001, P < .001, respectively). In multivariate regression analysis, SII and PLR were independent predictors of mortality (P = .031 and P < .001, respectively). In the receiver operating characteristics (ROC) curve analysis, the cutoff value for SII was ≥ 2951, and the area under the curve (AUC) was 0.662 (95% CI, 0.540–0.784). The cutoff value for NLR was ≥ 9.85, AUC was 0.717 (95% CI, 0.600–0.834), and the cutoff value for PLR was ≤ 130.4, AUC was 0.871 (95% CI, 0.796–0.947). 28-day mortality was 21.1%. Neuroinflammation is essential in patients with critical TBI, and inflammatory markers SII, NLR, and PLR have prognostic importance. SII and PLR are independent predictors of mortality. Early detection of those with a poor prognosis in critically ill TBI patients and planning aggressive treatments may contribute to reducing mortality.