In order to investigate the causal relationship between plasma proteins and pulmonary-derived sepsis using Mendelian randomization analysis. Bioinformatics and molecular docking technologies was employed for target prediction and identification of potential therapeutic agents, thereby providing valuable insights for the prevention and treatment of this condition.Summary data from large-scale genome-wide association studies were used to perform two-sample MR(multiple regression) analysis utilizing five methods: egger regression, weighted median, inverse variance weighted, simple mode, and weighted mode. Causal inference between plasma proteins and sepsis was evaluated based on the odds ratio (OR). Core target analysis, GO(gene ontology) enrichment, and KEGG(kyoto encyclopedia of genes and genomes) pathway analysis were conducted to explore the potential mechanisms of action between plasma proteins and pulmonary sepsis. Based on the core targets identified, potential therapeutic compounds were screened, and their binding affinities are validated through molecular docking. The results identifie 44 plasma proteins exhibiting significant associations with pulmonary-derived sepsis. Among these, 29 are identified as risk factors, positively associated with an increased disease risk, while the remaining 15 possessed protective effects, correlated with a reduced risk of sepsis. GO enrichment analysis reveals 182 biological processes, 128 cellular components, and 39 molecular functions. The KEGG enrichment results highlights several key pathways, including the Complement and Coagulation Cascades, Asthma, and the PI3K-Akt signaling pathway. The top ten identifie targets included LCN2, CHGA, and FBLN1. Six drugs, including medroxyprogesterone acetate, 5-azacytidine hydrate, and mifepristone, show strong interactions with the related targets. Pulmonary sepsis may be associated with multiple plasma proteins, and drugs such as medroxyprogesterone acetate could regulate plasma proteins, providing a potential strategy for the prevention and treatment of pulmonary sepsis.