Endometrial cancer (EnCa) poses a serious threat to the reproductive health of women worldwide. Lycorine, a natural plant-extract, exerts tumor-suppressive effects towards several cancers, yet its role and related mechanisms in EnCa are largely unknown. The present study first investigated whether lycorine exerts antitumor activity against EnCa cells and then explored the underlying mechanisms. Lycorine reduced viability and clonogenic growth, curtailed migration and invasion, and induced apoptosis in HEC-1-B cells in a concentration-dependent manner, while sparing human endometrial epithelial cells at lower concentrations. To probe the mechanism, we integrated network pharmacology and molecular docking, identifying 90 overlapping lycorine-endometrial cancer targets enriched in PI3K-AKT, NF-κB, mTOR, and NOD-like receptor pathways and predicting favorable binding to three hub proteins (MAPK1, PI3KCA, and CHUK). Consistent with these predictions, lycorine lowered MAPK1, PI3KCA, and CHUK protein levels and dampened downstream signaling. Notably, silencing PI3KCA largely blunted lycorine-induced growth inhibition, apoptosis, and motility changes, indicating that repression of PI3KCA is a key mediator of its effects. Collectively, these findings suggest that lycorine restrains the malignant behaviors of EnCa cells by suppressing PI3KCA-centered signaling and provide a rationale for further validation across additional models and for evaluating rational combinations.