Quorum-sensing molecules (QSMs) are secreted by bacteria to signal population density. Upon reaching a critical concentration， QSMs induce transcriptional alterations in bacteria， which enable virulence factor expression and biofilm formation. It is unclear whether mammalian hosts can recognize QSMs to trigger responsive antibacterial immunity. We report that mouse mast-cell-specific G-protein-coupled receptor Mrgprb2 and its human homolog MRGPRX2 are receptors for Gram-positive QSMs， including competence-stimulating peptide (CSP)-1. CSP-1 activates Mrgprb2 and MRGPRX2， triggering mast cell degranulation， which inhibits bacterial growth and prevents biofilm formation. Such antibacterial functions are reduced in Mrgprb2-deficient mast cells， while wild-type mast cells fail to inhibit the growth of bacterial strains lacking CSP-1. Mrgprb2-knockout mice exhibit reduced bacterial clearance， while pharmacologically activating Mrgprb2 in?vivo eliminates bacteria and improves disease score. These findings identify a host defense mechanism that uses QSMs as an "Achilles heel" and suggest MRGPRX2 as a potential therapeutic target for controlling bacterial infections.