Endoplasmic reticulum (ER) stress is commonly observed in intestinal epithelial cells (IEC) and can, if excessive, cause spontaneous intestinal inflammation as shown by mice with IEC-specific deletion of X-box binding protein-1 (Xbp1), an unfolded protein response (UPR)-related transcription factor. Here, Xbp1 deletion in the epithelium (Xbp1ΔIEC) is shown to cause increased expression of natural-killer group 2 member D (NKG2D) ligand (NKG2DL) murine UL16-binding protein like transcript 1 (MULT1) and its human orthologue cytomegalovirus UL16-binding protein (ULBP) via ER stress-related transcription factor C/EBP homology protein (CHOP). Increased NKG2DL expression on mouse IECs is associated with increased numbers of intraepithelial NKG2D-expressing group 1 ILCs. Blockade of NKG2D suppresses cytolysis against ER-stressed epithelial cells in vitro and spontaneous enteritis in vivo. Pharmacological depletion of NK1.1+ cells also significantly improved enteritis, while enteritis was not ameliorated in recombinase activating gene 1 (Rag1)–/–;Xbp1ΔIEC mice. These studies reveal innate immune sensing of ER stress in IEC as an important mechanism of intestinal inflammation.