Objective To explore serum protein biomarkers that are consistent with the pathological protein changes in the lungs of patients with pulmonary acute respiratory distress syndrome (P-ARDS). Method Healthy C57BL/6 mice of SPF grade were randomly divided into two groups using the random number table method: a control group and an ARDS experimental group. The ARDS experimental group received intratracheal injection of lipopolysaccharide (LPS), while the control group was administered an equal volume of saline via the same route. The models were established, and 24 hours later, both groups of mice were euthanized after anesthesia. Lung tissues from both groups were subjected to hematoxylin-eosin (HE) staining and wet-to-dry weight ratio (W/D) assessment to evaluate the ARDS disease model. Additionally, transcriptomics and proteomics sequencing were conducted on lung tissues from both the control and ARDS groups, and serum proteome sequencing was performed. These sequencing data were then jointly analyzed with the proteomic data of serum and lung tissue from patients with COVID-19-induced ARDS previously studied by our research group to identify serum protein biomarkers consistent with the pathological protein changes in the lung tissue. Results Compared to the control group, the pathological damage scores and lung wet-to-dry weight ratios in the ARDS experimental group mice were both significantly elevated (P0.05), indicating the successful establishment of the ARDS mouse disease model. A total of 28 differentially expressed proteins were identified that showed a consistent trend of change in both the lung tissue and serum of ARDS mice. Further integration with the proteomic sequencing results of lung tissue and plasma from ARDS patients led to the selection of four candidate proteins: haptoglobin (HP), S100 calcium-binding protein A9 (S100A9), serum amyloid A1 (SAA1), and serum amyloid A2 (SAA2), which were positively correlated with the severity of ARDS in patients. Conclusion The four candidate proteins, including HP, S100A9, SAA1, and SAA2, have the potential to serve as serum biomarkers reflecting the pathological changes in the lung tissue of ARDS patients and may have significant clinical value.