Pancreatic cancer (PC) remains one of the most aggressive malignancies, largely due to late diagnosis, rapid metastatic progression, and the limited efficacy of current therapeuties. Piperlongumine, a bioactive alkaloid isolated from Piper longum, has attracted attention for its selective cytotoxicity toward cancer cells and its ability to modulate multiple oncogenic pathways. However, its molecular mechanisms in PC remain insufficiently understood. In this computational systems pharmacology study, a network pharmacology strategy combined with molecular docking was used to investigate the molecular targets and pathways associated with piperlongumine’s anticancer activity. Targets of piperlongumine and PC-related genes were retrieved from public databases and intersected to identify shared targets. Overlapping targets were used to construct a proteinprotein interaction network using STRING platform. Hub genes were identified using the CytoHubba plugin using six topological algorithms. Functional enrichment analyses (Gene Ontology and KEGG pathways) were performed using ShinyGO 0.85 platform. Prognostic relevance of the hub targets was evaluated using Kaplan–Meier Plotter, while immune cell infiltration patterns were explored using TIMER. Molecular docking was conducted using AutoDock Vina to validate ligand-target interactions. A total of 237 intersecting genes were identified. Network analysis revealed several central hub genes, including TP53, Akt-1, STAT-3, CTNNB-1, IL-6, TNF-α, and Bcl-2. KEGG pathway analysis highlighted PC as the most enriched pathway, together with the PD-1/PD-L1 pathway, TNF signaling, and other cancer-related pathways. Survival analysis revealed significant prognostic associations for several hub genes, while TIMER analysis suggested correlations with tumor-associated immune cell infiltration. Molecular docking confirmed favorable binding affinities of piperlongumine toward key oncogenic targets, particularly Bcl-2 (-7.2 kcal/mol), TP53 (-6.2 kcal/mol), CTNNB-1 (-6.2 kcal/mol), and Akt-1 (-5.8 kcal/mol). Collectively, this study uncovers piperlongumine's anticancer potential in PC, mediated through coordinated regulation of apoptosis, inflammatory, and immune pathways, highlighting its promise for future experimental and translational investigations.