Abstract Purpose Based on the hypothesis that systemic inflammation contributes to secondary injury after initial traumatic brain injury (TBI), this study aims to describe the effect of splenectomy on mortality in trauma patients with TBI and splenic injury. Methods A retrospective cohort analysis of patients prospectively registered into the TraumaRegister DGU^® (TR-DGU) with TBI (AIS_Head ≥ 3) combined with injury to the spleen (AIS_Spleen ≥ 1) was conducted. Multivariable logistic regression modeling was performed to adjust for confounding factors and to assess the independent effect of splenectomy on in-hospital mortality. Results The cohort consisted of 1114 patients out of which 328 (29.4%) had undergone early splenectomy. Patients with splenectomy demonstrated a higher Injury Severity Score (median: 34 vs. 44, p < 0.001) and lower Glasgow Coma Scale (median: 9 vs. 7, p = 0.014) upon admission. Splenectomized patients were more frequently hypotensive upon admission (19.8% vs. 38.0%, p < 0.001) and in need for blood transfusion (30.3% vs. 61.0%, p < 0.001). The mortality was 20.7% in the splenectomy group and 10.3% in the remaining cohort. After adjustment for confounding factors, early splenectomy was not found to exert a significant effect on in-hospital mortality (OR 1.29 (0.67–2.50), p = 0.45). Conclusion Trauma patients with TBI and spleen injury undergoing splenectomy demonstrate a more severe injury pattern, more compromised hemodynamic status and higher in-hospital mortality than patients without splenectomy. Adjustment for confounding factors reveals that the splenectomy procedure itself is not independently associated with survival.