Objective To investigate the efficacy of sivelestat sodium in patients with severe acute pancreatitis (SAP) combined with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and prognosis. Methods Patients with severe acute pancreatitis and ALI/ARDS, who were admitted to the Intensive Care Unit, the Affiliated Hospital of Xuzhou Medical University from September 2020 to September 2023 were selected. According to the use of sivelestat sodium, they were divided into two groups: a control group and an intervention group. Using the propensity score matching method, the patients were matched at 1∶1, with 55 patients in each group. Their baseline data, including sex, age, etiology, continuous renal replacement therapy (CRRT), and the Acute Physiology and Chronic Health Evaluation (APACHEⅡ) scores at admission were recorded. Both groups were compared for blood lactic acid (Lac), oxygenation index (OI), alanine transaminase (ALT), total bilirubin (TBIL), creatinine (Cr), blood urea nitrogen (BUN), blood amylase (AMY), C‑reactive protein (CRP) and interleukin‑6 (IL‑6) before and after treatment. Furthermore, the differences in 28‑day ventilator‑free days (VFD), the length of intensive care unit (ICU) stay, non‑ICU hospitalization days within 28 d, and 28‑day mortality were assessed between the two groups. Results There were no statistical differences in sex ratio, age, etiology, CRRT, or APACHE Ⅱ scores at admission between the two groups (all P>0.05). Compared with those before treatment, both group showed decreases in Lac, CRP, and IL‑6 (all P<0.05), and increases in OI (P<0.05). The control group presented decreased ALT, Cr, and AMY (all P<0.05), and increased BUN (P<0.05), while decreased Cr and AMY (all P<0.05) were seen in the intervention group. After treatment, the intervention group had higher OI and lower CRP and IL‑6 levels than control group (all P<0.05). No statistical differences were found in Lac, ALT, TBIL, Cr, BUN, and AMY in both groups before and after treatment, and in OI, CRP, and IL‑6 in both group before treatment (all P>0.05). Compared with the control group, the intervention group showed increased 28‑day VFD (P<0.05), without statistical differences in the length of ICU stay, non‑ICU hospitalization days within 28 d, or 28‑day mortality (all P>0.05). Conclusions Sivelestat sodium can be safely used in the treatment of patients with severe acute pancreatitis combined with ALI/ARDS. It effectively improves inflammation and oxygenation index, and increases 28‑day VFD, but does not shorten the length of ICU stay or reduce 28‑day mortality.