Objective: To investigate the effect of Shenlingbaizhu powder (SBP) on cigarette smoke-induced chronic obstructive pulmonary disease (COPD) in mice. Methods: 24 male BALB/c mice were randomly divided into four groups: control group, COPD group, low-dose SBP group (L-SBP group), and high-dose SBP group (H-SBP group). A COPD mouse model was established by combined exposure to lipopolysaccharide (LPS) and cigarette smoke (CS). After modeling, the L-SBP and H-SBP groups were administered SBP via oral gavage at doses of 1.72g/kg and 3.44g/kg, respectively, while the control and COPD groups received equal volumes of normal saline. Treatment continued for 8 weeks. After treatment, hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemistry were used to observe pathological changes in lung tissue. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Transcriptomic sequencing (RNA-seq) was performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA), gene ontology (GO) functional analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Western blot (WB) was used to validate the expression levels of key pathway proteins in lung tissue. Results: SBP significantly alleviated the pathological features of COPD induced by CS/LPS in mice. Furthermore, SBP treatment reduced the expression of Caspase-3 and α-SMA proteins and increased Ki67 protein levels. SBP also decreased serum levels of TNF-α, IL-1β, and IL-6, with more pronounced effects at the high dose. Transcriptomic analysis revealed that SBP treatment notably influenced the Rap1 signaling pathway. SBP up-regulated the expression of key proteins in the Rap1 pathway, including Rap1, HGF, and Angpt2. Conclusion: SBP inhibits the inflammatory response in COPD by activating the Rap1 signaling pathway.