Background: The objective of this research was to explore the correlation between serum sirtuin 6 (SIRT6) levels and neurological dysfunction, as well as the prognosis following early traumatic brain injury (TBI). Methods: As a retrospective analysis, the study involved 103 severe TBI patients admitted to our hospital, while 103 additional non-traumatic brain injury (non-TBI) patients from the same timeframe served as the control group. After one month post-injury, patients in the trauma cohort were categorized into two groups based on the Glasgow prognostic score (GOS): a group with favorable prognosis (62 cases) and a group with unfavorable prognosis (41 cases). Results: Patients in the TBI group had substantially lower serum SIRT6 levels than those in the non-TBI group (t = 9.335, p < 0.001). Following an early TBI, SIRT6 levels were positively correlated (r = 0.566, p < 0.001) with GOS scores and negatively correlated (r = −0.557, p < 0.001) with the National Institutes of Health Stroke Scale (NIHSS) scores, according to Spearman’s correlation analysis. Patients in the poor prognosis group had lower Glasgow Coma Score (GCS), SIRT6 and GOS scores at admission, and higher NIHSS scores and Rotterdam computed tomography (CT) scores than those in the good prognosis group at 1 month post-injury (p < 0.05). The area under the curve (AUC) of serum SIRT6 was 0.942 (95% confidence interval (CI): 0.878–0.979). NIHSS score (odds ratio (OR) = 1.964, p = 0.016), Rotterdam CT score (OR = 57.995, p = 0.013), GCS score (OR = 0.300, p = 0.015), and serum SIRT6 level (OR = 0.025, p = 0.006) were significant determinant factors for poor prognosis in patients with early TBI. Conclusions: Serum SIRT6 was significantly lower in patients with early TBI and was associated with neurological impairment as well as poor prognosis.