Background: Multi-organ distress syndrome (MODS) causes morbidity in patients with trauma. This study evaluates the effectiveness of interleukin-33 (IL-33), which reflects tissue damage and the inflammatory response, as a MODS indicator in patients with trauma. Methods: Patients with trauma admitted to our trauma center between July 2022 and July 2023 were included. IL-33 levels were measured in blood samples for 4 days. Correlations with clinical and laboratory indicators, including initial IL-33 levels, were analyzed to identify independent predictors of MODS. Results: Among the 87 patients enrolled, 20 developed MODS. Initial IL-33 levels were elevated in the MODS group, compared with the non-MODS group. In the non-MODS group, IL-33 levels increased on day 1 and then declined, whereas in the MODS group, IL-33 levels were highest at admission (day 0) and decreased continuously through day 3. In patients with detectable initial IL-33 levels, the measured levels correlated with higher Abbreviated Injury Scale 5 scores and the Injury Severity Score (ISS). A logistic regression analysis revealed the ISS and delta neutrophil index as factors contributing to MODS progression. Conclusions The findings suggest that initial IL-33 levels are elevated in the MODS group, compared with non-MODS group, and exhibit a rapidly declining trend, showing an initial association with MODS that was not maintained in a multivariate analysis. These findings suggest that IL-33 might have relevance in assessing trauma severity; however, further validation is required before it can be considered a biomarker for MODS.