Vitamin D exerts a regulatory role over mucosal immunity via the vitamin D receptor (VDR). While Paneth cells and their products are known to regulate the commensal and pathogenic microbiota, the role that VDRs in Paneth cells play in these responses is unknown.We identified the decreased intestinal VDR significantly correlated with reduction of an IBD risk gene ATG16L1 and Paneth cell Lysozymes in patients with Crohn's Disease. We generated a Paneth cell specific VDR knockout (VDRΔPC) mice to investigate the molecular mechanisms. Lysozymes in the Paneth cells were significantly decreased in the VDRΔPC mice. Isolated VDRΔPC Paneth cells exhibited weakened inhibition of pathogenic bacterial growth and displayed reduced autophagic responses. VDRΔPC mice had significantly higher inflammation after Salmonella infections. VDRΔPC mice also showed high susceptibility to small intestinal injury induced by indomethacin, a nonsteroidal anti-inflammatory drug. Co-housing of VDRΔPC and VDRloxp mice made the VDRΔPC less vulnerable to the DSS-colitis, suggesting the transmission of protective bacterial from the VDRloxp mice. Thus, a lack of VDR in Paneth cells leads to impaired anti-bacterial activities and consequently increased inflammatory responses. Genetically and environmentally regulated VDRs in the Paneth cells may set the threshold for the development of chronic inflammation, as observed in inflammatory bowel diseases.We provide new insights into the tissue-specific functions of VDRs in maintaining the Paneth cell alertness to pathogens in intestinal disorders. Targeting the VDR affects multiple downstream events within Paneth cells that inhibit intestinal inflammation and establish host defense against enteropathogens.