Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Banzhilian (BZL) and Baihuasheshecao (BHSSC) are classical Chinese herbs used in tumor therapy. However, the underlying mechanisms of BZL-BHSSC in treating PDAC have not been identified. Combining network pharmacology with single-cell RNA sequencing (scRNAseq), this study systematically explored the potential mechanisms of BZL-BHSSC in the treatment of PDAC. Methods: The bioactive ingredients of BZL-BHSSC were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, while the PDAC-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Based on the dataset GSE62452, we adopted differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen the signature genes of PDAC. To reveal the cell types of the pharmacological targets of BZL-BHSSC against PDAC, we performed scRNA-seq analysis and principal component analysis (PCA) on the dataset GSE111672. Molecular docking and immunohistochemical staining were used to validate our initial results. Results: We obtained 29 bioactive ingredients from BZL-BHSSC and screened 210 signature genes of PDAC. Using network pharmacology, we identified 7 key therapeutic targets CDK1, MYC, CCNB1, TOP2A, CLDN4, NUF2, and MET, revealing that baicalein, quercetin, and luteolin are core components for the efficacy of BZL-BHSSC. The main signaling pathways involved in therapy were the PI3K-AKT signaling pathway and the p53 signaling pathway. The molecular docking results verified the strong binding activity (binding energy > -7 kJ/mol) between active ingredients and targets. The scRNA-seq results informed that cells from 3 PDAC samples could aggregate into 19 clusters and 3 cell types. The target genes were almost concentrated on the immune cells. Immunoinfiltration analysis suggested that the expression of Macrophages M0 and Dendritic cells activated was significantly upregulated in the PDAC group (p< 0.001), while the opposite was true for B cells naïve and T cells CD8 expression (p< 0.05). Conclusion: We concluded that BZL-BHSSC can improve the overall survival prognosis of PDAC patients by interfering with the signature genes of PDAC through direct and indirect pathways and improving immunity. Our study provides a basis for subsequent studies.