Apoptosis among intestinal epithelial cells contributes to necrotizing enterocolitis (NEC), a severe intestinal disease that particularly affects premature infants. β-arrestin-2, an important regulator of G-protein-coupled receptors, is expressed in intestinal epithelial cells, where its activation promotes apoptosis. We found that β-arrestin-2 was overexpressed in both human and murine NEC samples. β-arrestin-2-deficient mice were protected from endoplasmic reticulum stress and NEC development. The endoplasmic reticulum-resident chaperone BiP was found to promote intestinal epithelial cell survival. Pretreatment of intestinal epithelial cells or mice with the BiP inhibitor HA15 increased cell apoptosis and promoted NEC development. β-arrestin-2 bound to BiP and promoted its polyubiquitination and degradation, thereby facilitating the release of the pro-apoptotic molecule BIK from BiP. Silencing β-arrestin-2 downregulated apoptosis by increasing BiP levels, which suppressed endoplasmic reticulum stress. This study suggests that β-arrestin-2 induces NEC development by inhibiting BiP, thereby triggering apoptosis in response to endoplasmic reticulum stress. Thus, novel therapeutic strategies to inhibit β-arrestin-2 may enhance the treatment of NEC.