Intestinal barrier loss in patients with inflammatory bowel disease (IBD) is associated with reduced expression of the tight junction protein occludin. Yet, the relatively-normal basal phenotype of occludin knockout (KO) mice has been taken as evidence that occludin may not contribute to gastrointestinal barrier function. We asked whether adding stress could unmask occludin functions within intestinal murine epithelia, and further investigated the function of occludin in cell lines and patient biopsies. We find occludin increases expression of caspase-3, which induces apoptosis. Reduced occludin expression leads to caspase-3 downregulation that limits epithelial apoptosis and attenuates colitis. Occludin downregulation correlates with lower levels of caspase-3 expression in biopsies from patients with IBD. These data put forward a previously unappreciated anti-apoptotic process that contributes to mucosal homeostasis in inflammatory conditions. Moreover, occludin downregulation by inflammatory stimuli may be a mechanism of epithelial preservation that promotes mucosal homeostasis.