Severe injuries caused by accidents, like traumatic brain injury (TBI) or thoracic trauma (TT) continue to be the leading cause of death in younger people with relevant socio-economic impact. Fast and targeted diagnostics is essential for further therapy decisions and prognosis. The following study investigates NSE as a potential biomarker for lung injury after blunt TT. This is a retrospective analysis of prospectively collected data in a level-1 trauma center from 2014 to 2020. Serum levels of Neuron-specific Enolase (NSE) and Interleukins (IL-6, IL-10) in injured patients (n = 41) with isolated TT (AISthorax ≥ 3) compared to isolated TBI (AIShead ≥ 3) were assessed from day 0 to 5 after trauma. The extend of lung injury was quantified by Hounsfield scale in CT scans. 30 patients with TT (ISSmed = 20, age 50y ± 17, 83,3% male) and 11 patients with TBI (ISSmed = 25, age 54y ± 17,27,3% male) were included. After TT, NSE concentration increased initially after trauma with a peak value on the day of admission (8.51 ± 3.68 ng/ml) compared to healthy controls (4.51 ± 1.504 ng/ml, p < 0.001). Isolated thoracic trauma and TBI lead to equally strong NSE release ad the day of admission. There is a significant linear relationship (r = 0.636, p = 0.035) between serum NSE levels and severity of pulmonary contusion at the time of admission and after 24 hours. A significant NSE release after isolated thoracic trauma peaks on the day of admission. The extent of lung contusion volume (defined as alveolar parenchymal density) correlates with NSE serum concentration. Thus, NSE has predictive value for the extent of pulmonary contusion. However, according to these data, NSE seems to have no diagnostic value as a TBI biomarker in concomitant TT.