Protease-activated receptor 2 (PAR2) regulates tumor progression via cancer cell proliferation, migration, invasion, and metastasis. PAR2 overexpression correlates with poor prognosis, making it a therapeutic target. However, existing antagonists exhibit limited efficacy with no clinical success, focusing on signal inhibition without receptor regulation. We show that punicalagin (PCG), a pomegranate polyphenol, exerts a dual mechanism: inhibiting PAR2 signaling while promoting PAR2 internalization and lysosomal trafficking, unlike conventional antagonists. PCG demonstrated potent antagonism in HT29 cells, with anticancer effects characterized in HT29 and MDA-MB-231 cells as PAR2-associated cancer models. To confirm internalization's role, Pitstop2, a clathrin endocytosis inhibitor, was used. Pitstop2 pretreatment blocked internalization and reduced PCG's antagonism, increasing the IC₅₀ for calcium signaling threefold. PCG's effects on viability, migration, and apoptosis were significantly reduced. These findings show punicalagin-driven internalization drives its antagonism and anticancer activity, highlighting this as a promising strategy for PAR2-overexpressing cancers.