Objective To predict the target of the main components of Qingyi Huaji recipe (QYHJ) through network pharmacology investigations, and to explore its mechanism in treating pancreatic cancer. Methods The Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) database was used to identify the major effective components of QYHJ and their target genes. The xenograft model of pancreatic cancer was established in nude mice, and they were divided into QYHJ-treated group and control group. The tumor tissues of nude mice were sequenced to screen the differentially expressed genes. The target genes were screened by Venn analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify the related pathways; then the regulatory mechanism network of QYHJ in treating pancreatic cancer was constructed. The protein-protein interaction network was obtained from the STRING database, and Gene Expression Profiling Interactive Analysis (GEPIA) was used to evaluate the relationship between the key genes and the prognosis of pancreatic cancer. Results A total of 149 potential active components and 963 predicted targets were obtained. Gene sequencing of pancreatic cancer tissues of nude mice (QYHJtreated group vs control group) showed 6 039 differentially expressed genes. Venn analysis showed 248 potential targets and KEGG pathway enrichment analyses found that the mechanism of QYHJ in treating pancreatic cancer might involve mitogenactivated protein kinase (MAPK), forkhead box O (FoxO), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate-dependent protein kinase or protein kinase G (cGMP-PKG) and other signaling pathways. Compared with the control group, the QYHJ-treated group showed suppressed MAP2K1 (MEK1), MAPK3 (ERK), MAP2K3 (MKK3), and MAPK13 (p38) expressions. GEPIA results showed that the high expression levels of MAP2K1 (MEK1), MAPK3 (ERK), MAP2K3 (MKK3) and MAPK13 (p38) were related to the poor prognosis of pancreatic cancer patients. Conclusion The mechanism of QYHJ in treating pancreatic cancer may be related to MAPK signaling pathways. MAP2K1 (MEK1), MAPK3 (ERK), MAP2K3 (MKK3) and MAPK13 (p38) may be potential prognostic factors of QYHJ for treating pancreatic cancer.