Objective: This study aims to investigate the potential mechanism of cucurbitacin E in the treatment of Pancreatic adenocarcinoma (PAAD) using network pharmacology and molecular docking technology. Methods: We collect the action targets of cucurbitacin E from Swiss Target Prediction, Pharmmapper and TargetNet databases. Additionally, we obtained PAAD-related targets from GeneCard, OMIM, PharmGKB, DrugBank and TTD databases. The intersection targets of cucurbitacin E and PAAD was regarded as potential therapeutic targets against PAAD, the protein-protein interaction network was constructed by using String database and Cytoscape software, and the David database was used for GO and KEGG enrichment analysis. Then performed molecular docking of cucurbitacin E with the core target proteins using LeDock software. Analyze the expression differences of core genes in PAAD using the GEPIA database; explore the relationship between core gene expression and the survival time of PAAD patients as well as tumor immune infiltration using the TIMER database, and conduct SMART database analysis on the methylation of core genes. Results: 97 potential targets of Cucurbitacin E against PAAD were identified, among which the top ten core targets were SRC, HRAS, HSP90AA1, Alb, ANXA5, MMP9, IGF1, CASP3, MAPK1 and EGFR. GO enrichment analysis shows 62 biological processes, 19 cellular components, and 17 molecular functions. KEGG enrichment analysis identifies 90 signaling pathways. Molecular docking results indicate that Cucurbitacin E shows strong affinity with most core target proteins. In addition, gene differential expression, survival analysis, immune infiltration and methylation analysis suggest that the core targets MAPK1 and CASP3 may serve as biomarkers for the prognosis of PAAD treatment. Conclusion: This study theoretically elucidates the potential molecular mechanisms of Cucurbitacin E in the treatment of PAAD through methods such as network pharmacology and bioinformatics, providing theoretical support and reference for subsequent basic experiments and clinical research.