Death of intestinal epithelial cells (IECs) is important in the pathological process of intestinal inflammatory diseases. TNF acts as one pathogenic driver for inducing IEC death and substantial intestinal inflammation. However, the physiological protective mechanisms for suppressing TNF-induced IEC death remain poorly understood. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects the intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin to suppress the phosphorylation of Cofilin, leading to the inhibition of TNF receptor Ⅰ (TNFR1) internalization and TNF-induced apoptosis. Our findings define EFHD2 as an endogenous suppressor of IEC death to protect intestine inflammation, providing new insight to the regulation of death receptor signaling and control of intestinal inflammatory diseases.