Ulcerative colitis (UC) is usually a mildly active disease; however, it can be associated with serious systemic complications. The current study was undertaken to evaluate the anti-ulcerogenic and coloprotective properties of crocin; the major biologically active ingredient of saffron against experimentally-induced UC, by intracolonic instillation of AA (AA). Rats received either felodipine (3 mg/kg) or crocin (20 mg/kg) orally for 8 successive days as protective and curative therapies. Either as a protective or as a curative remedy, crocin significantly reversed AA-induced colonic damage. Intracolonic AA-induced a significant functional, biochemical and inflammatory colon injury. On the other hand, crocin significantly attenuated AA-induced oxidative, inflammatory and apoptotic activity. Crocin significantly enhanced colon anti-oxidant defenses and reduced colon tumor necrosis factor-α (TNF-α) and Ca+2 contents with down-regulation of the inflammatory response and oxidative load. The anti-ulcerogenic effect of crocin appears to be Ca+2 dependent. Most importantly, crocin enhanced colon Nuclear Factor, Erythroid-Derived 2 like Protein 2 (Nrf2) content and Heme Oxygenase-1 (HO-1) activity and attenuated caspase-3 activity. In conclusion; crocin demonstrated anti-ulcerogenic and coloprotective effect mediated primarily by its antioxidant, anti-inflammatory and anti-apoptotic properties. The therapeutic impact is mediated primarily via enhancement of colon Nrf2 content by 211% in protective protocol and by 350% in curative and HO-1 signaling by 49% in protective protocol and, 288% in the curative protocol. Enhancement of Nrf2 and HO-1 signaling and down-regulation of caspase-3 activity are believed to underly the observed therapeutic effect.