Objective: To explore the effects of sivelestat sodium hydrate on scores of acute physiology and chronic health evaluation II (APACHE II) and levels of serum C-reactive protein (CRP), interleukin-6 (interleukin-6) and tumor necrosis factor-α (TNF-α) in patients with severe pneumonia (SP) and system inflammatory reaction syndrome (SIRS). Methods: A total of 82 patients with SP and SIRS who were confirmed in the hospital were enrolled between July 2021 and December 2024. were selected. According to random number table method, they were divided into control group (routine treatment) and sivelestat sodium group (injection of 4.80 mg.kg_-1^.d_-1 ^{sivelestat sodium hydrate} on basis of control group), 41 cases in each group. All patients were treated continuously for 14d. The clinical curative effect, remission time of symptoms, APACHE II scores, levels of inflammatory factors (CRP, IL-6, TNF-α) and adverse reactions were compared between the two groups. Results: After treatment, response rate of sivelestat sodium group was higher than that of control group [85.37% (35/41) vs 65.85% (27/41), P<0.05]. The recovery time of body temperature, heart rate and respiratory rate in sivelestat sodium group was all shorter than that in control group (P<0.05). After treatment, APACHE II score, levels of CRP, IL-6 and TNF-α were decreased in both groups, which were lower in sivelestat sodium group than control group (P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Conclusion: On basis of routine treatment, sivelestat sodium hydrate can significantly improve clinical curative effect, effectively improve APACHE II score and levels of serum CRP, IL-6 and TNF-α in patients with SP and SIRS.