The polymeric immunoglobulin (Ig) receptor-like (pIgRL) molecules have been identified in teleost fish. However, compare to the functional studies of their related genes (mammalian CD300 family, et al) in eliminating pathogen invasion while preserving homeostasis, the roles of pIgRL in teleost fish remain unclear. In this study, we demonstrated that a pair of pIgRL molecules in zebrafish, pIgRL3.5 and pIgRL4.2, were highly expressed in the intestine and immune cells. Moreover, we constructed an Edwardsiella piscicida infection model, which induced strong inflammatory responses in the zebrafish intestine. Interestingly, pIgRL3.5 and pIgRL4.2 exhibited opposite inducible expression patterns in response to bacterial infection, suggesting that they perform different roles. More importantly, by conducting overexpression and knockdown experiments, our findings demonstrated that zebrafish pIgRL3.5 played a protective role in the host defense against E. piscicida infection by inhibiting excessive inflammatory responses. In contrast, pIgRL4.2 facilitated pathogen growth and dissemination in zebrafish intestine. Collectively, our findings were the first to demonstrate that a pair of pIgRL molecules in teleost fish play opposite roles in mucosal immune response to bacterial infection. Therefore, our results provide crucial insights into the conserved role of pIgRL molecules in immune regulatory functions throughout vertebrate evolution.