Polycomb Repressive Complex 2 (PRC2) is a multi-subunit complex responsible for tri-methylating histone H3 at lysine 27 (H3K27me3), which marks gene silencing. Dysregulation of PRC2, particularly through the overexpression of its component EZH2, is linked to cancers and developmental disorders. Inhibiting EZH2 activity can reduce cancer cell proliferation and tumorigenesis, making it a target for drug development. In this study, we screened over two thousand compounds and identified pyrroloquinoline quinone (PQQ) as a potent PRC2 methyltransferase inhibitor in vitro. We assessed PQQ's anti-tumor effects across various cell lines and found strong activity against B cell lymphoma cells with elevated EZH2 levels. Notably, PQQ is a naturally occurring compound with antioxidant and neuroprotective properties, approved as a dietary supplement in the U.S. This study highlights that PQQ, used as a dietary supplement, inhibits PRC2 methyltransferase activity, offering new insights for targeted anti-lymphoma therapies.