Lentinula edodes (LE) is known as a good food source with potent anticancer efficacy, but its active compounds and mechanisms against cancer have not been revealed. The aim of this study was to investigate the bioactive compounds and mechanisms of LE against cancer via network pharmacology. Compounds from LE were detected by Gas Chromatography Mass Spectrometry (GC-MS) and screened as drug-like compounds by SwissADME. Targets were identified by two public bioinformatics, and overlapping targets were selected by Venn diagram. Then, protein-protein interaction (PPI) and pathways-targets-compounds (PTC) networks were constructed by RStudio. Lastly, we identified key compounds and targets via molecular docking test (MDT) on AutoDockVina. A total of 34 compounds from LE were selected as drug-like compounds (DLCs). The 34 compounds were associated with 108 targets and a key target (COX2) was identified through PPI networks. Most significantly, out of 9 pathways, inactivation of Pathways in cancer and activation of Peroxisome Proliferator Activated Receptor (PPAR) signaling pathway were uppermost pathways of LE. On MDT, we identified a key compound (Indole, 2-methyl-3-phenyl) on COX2 related to inactivation of Pathways in cancer. Additionally, the number of 6 ergostane steroids associated with both pathways might be dual efficacy to alleviate inflammation against cancer. Overall, 13 targets, 11 compounds, 2 key pathways of LE were identified as the primary elements to treat cancer. Therefore, this study provides therapeutic evidence to evaluate the promising clinical efficacy of LE on cancer, suggesting that LE is a good food pharmacy with synergistic effects against cancer.