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A recent single-cell survey of the small-intestinal epithelium suggests that mucosal pentraxin 2 (Mptx2) is a new Paneth cell marker, but its function and involved mechanism in the Paneth cell are still unknown. Therefore, we create Mptx2 knockout (Mptx2−/−) mice to investigate its precise effects on intestinal homeostasis using models of lipopolysaccharide (LPS), methicillin-resistant Staphylococcus aureus (MRSA) peritoneal infection, and dextran sulfate sodium (DSS)–induced intestinal injury and inflammation. We here find that Mptx2 is selectively expressed in Paneth cells in the small intestines of mice. Mptx2−/− mice have increased susceptibility to intestinal inflammation and injured. Mptx2 deficiency reduces Paneth cell count and expression of antimicrobial factors, leading to altered intestinal bacteria composition. Loss of Mptx2 aggravates MRSA infection–induced damage in the intestine while decreasing autophagy in Paneth cells. Mptx2−/− mice are more vulnerable to LPS-induced intestinal possibly due to inhibition of the autophagy/endoplasmic reticulum (ER) stress pathway. Mptx2−/− mice are susceptible to DSS-induced colitis that could be ameliorated by treatment with gentamicin or vancomycin antibiotics. In conclusion, Mptx2 is essential to maintain intestinal homeostasis potentially via regulation of autophagy in Paneth cells. Mucosal pentraxin 2 (Mptx2) is identified as a marker of Paneth cells, and its deficiency is shown to trigger microbiota dysbiosis and increased epithelial invasion by bacteria while also reducing secretory autophagy. [ABSTRACT FROM AUTHOR]