The molecular mechanisms that restore intestinal epithelial homeostasis during colitis are incompletely understood. Here, we report that during intestinal inflammation, multiple inflammatory cytokines promote the activity of a master regulator of cell proliferation and apoptosis, serine/threonine kinase CK2. Enhanced mucosal CK2 protein expression and activity were observed in animal models of chronic colitis, particularly within intestinal epithelial cells (IECs). The in vitro treatment of intestinal epithelial cell lines with cytokines resulted in increased CK2 expression and nuclear translocation of its catalytic alpha subunit. Similarly, nuclear translocation of CK2alpha was a prominent feature observed in colonic crypts from individuals with ulcerative colitis and Crohn's disease. Further in vitro studies revealed that CK2 activity promotes epithelial restitution, and protects normal IECs from cytokine-induced apoptosis. These observations identify CK2 as a key regulator of homeostatic properties of the intestinal epithelium that serves to promote wound healing, in part through inhibition of apoptosis under conditions of inflammation.