Background: Sanghuangporus vaninii has antioxidant, anti-inflammatory, anti-tumor and other effects. However, the antitumor effects and mechanisms of S.vaninii gainst pancreatic cancer remain unclear. Methods: The antitumor activity of compounds isolated from S. vaninii was evaluated, and cell function experiments, such as wound healing, transwell and 3D culture assays, were conducted after the target cancer species was determined. Transcriptome analysis, Micro-Scale Thermophoresis and western blot were used to verify the targets and signaling pathways. Results: 13 compounds were isolated and identified from S.vanini. Among them, compound 1, the phenylpentane derivative compound, has the strongest inhibitory activity on the pancreatic cancer cells. In vitro, compound 1 inhibited the proliferation, migration, invasion, tube formation and colony formation of PANC-1 cells in a dose-dependent manner. Through transcriptome analysis, the signaling pathways compound 1 targeted were identified as MAPK/PI3K and HIPPO pathways. Western blot and immunofluorescence assay also showed that compound 1 can inhibit the EMT through inactivated HIPPO signaling pathway. By molecular docking and MST assay, we confirmed that compound 1 interacted with EGFR by binding with LYS745/PHE856 of EGFR. After knocking down EGFR, the effect of compound 1 on downstream signaling pathways was weakened, and the functions such as migration and invasion of cancer cells were also decreased. Conclusion: Compound 1, the phenylpentane derivative isolated from S. vaninii, inhibited the malignant process and EMT in PANC-1 cells via MAPK/PI3K and HIPPO signaling pathways by targeting EGFR. These data indicated that compound 1 might be a potential drug candidate for pancreatic cancer treatment.