Background/Objectives: Interleukin-32 (IL-32) is a pro-inflammatory cytokine primarily produced by immune cells and involved in bacterial and viral infections. This study investigates whether plasma IL-32 is associated with sepsis severity and clinical outcomes. Methods: Plasma IL-32 levels were measured in 186 patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock, as well as in 40 controls. The relationship between IL-32 levels and SARS-CoV-2 or bacterial infections, alongside underlying etiological conditions, was assessed. Results: Patients with liver cirrhosis exhibited elevated plasma IL-32 levels. After excluding these patients, IL-32 levels were lower in SIRS/sepsis patients compared to the controls. No significant differences in IL-32 levels were observed among SIRS, sepsis, and septic shock patients. Additionally, underlying conditions such as pancreatitis and cholangitis did not influence IL-32 levels. Patients with bloodstream bacterial infections, SARS-CoV-2 infections, or no documented infection had comparable IL-32 levels. Notably, higher IL-32 levels were associated with increased mortality. Conclusions: These findings suggest that a reduction in plasma IL-32 levels may be protective in SIRS/sepsis patients, as elevated levels are linked to poor survival outcomes.