OBJECTIVES: Traumatic brain injury (TBI) is a critical public health issue with high mortality and disability rates. Current diagnostic tools lack sensitivity and specificity, under-scoring the need for novel biomarkers. This study aimed to evaluate the clinical utility of NLRP3, ASC, and Caspase-1 as biomarkers for assessing TBI severity and prognosis. METHODS: A prospective cohort of 89 patients with moderate-to-severe TBI was studied. Blood and cerebrospinal fluid (CSF) samples were collected for four consecutive days post-injury. Levels of NLRP3, ASC, and Caspase-1 were measured using enzyme-linked immunosorbent as-say (ELISA). Statistical analyses, including ROC curve analysis, were conducted to assess their predictive performance. RESULTS: NLRP3, ASC, and Caspase-1 levels in both serum and CSF were significantly elevated in TBI patients, with higher levels correlating with greater injury severity. ROC analysis revealed that CSF biomarkers, particularly NLRP3, demonstrated superior predictive value. CSF NLRP3 levels on days 1, 2, and 4 had AUC values of 0.9871, 0.9466, and 0.8967, respectively. Dynamic changes in these biomarkers over time provided insights into disease progression and prognosis. Serum markers, while less predictive than CSF, were also effective for assessing injury severity. CONCLUSIONS: NLRP3, ASC, and Caspase-1 are promising biomarkers for evaluating TBI severity and predicting outcomes. Their dynamic monitoring may improve clinical management and in-form therapeutic strategies. Future research should validate these findings in larger cohorts and explore interventions targeting these inflammatory pathways.