Introduction. In trauma patients, the development of sepsis as a hospital complication is significantly associated with morbidity and mortality. We aimed to assess the risk factors associated with in-hospital mortality among trauma patients who developed sepsis during their hospital stay. Material and methods. Using the 2017 National Trauma Data Bank, a retrospective cohort study was conducted to identify adult trauma patients who developed sepsis during their hospital stay. The primary outcome of interest was in-hospital mortality. Multivariate analysis was used to determine the risk factors associated with in-hospital mortality. Results. 1782 trauma patients developed sepsis. 567 patients (31.8%) died during their hospital stay. The following patient factors were associated with higher odds of in-hospital mortality: age (OR = 1.045 95% CI = 1.036–1.054), chronic renal failure (OR = 2.564 95% CI = 1.528–4.301), and liver cirrhosis (OR = 3.699 95% CI = 2.267–6.033). Patients who developed cardiac arrest (OR = 4.994 95% CI = 3.381–7.378), acute kidney injury (OR = 3.808 95% CI = 2.837–5.110), acute respiratory distress syndrome (OR = 1.688 95% CI = 1.197–2.379), and stroke (OR = 1.998 95% CI = 1.075–3.714) during their hospital stay had higher odds of mortality. Higher Glasgow Coma Scale (13–15) at presentation was associated with lower odds of mortality (OR = 0.467 95% CI = 0.328–0.667). Conclusion. Among trauma patients who developed sepsis, age, chronic renal failure, cirrhosis, the development of cardiac arrest, acute kidney injury, acute respiratory distress syndrome, and stroke in the hospital were associated with in-hospital mortality. These factors can be used to identify patients who are at higher risk of adverse outcomes and implement standardized or protocol-driven methods to improve patient care.