Ulcerative colitis is a progressive disabling inflammatory bowel disease characterized by idiopathic, repetitive, and diffuse inflammation of the mucosa of the colon and the rectum. The pathogenesis of UC includes continuous inflammation of the colonic lamina propria, with damage of the mucosal barrier and infiltration with inflammatory factors. The underlying etiology of UC is still unclear. In this study, thirty adult male albino rats (150-200 g) were divided into 3 equal groups; group I (control), group II (subjected to intra-colonic instillation of 5% acetic acid for 3 consecutive days), and group III (received acetic acid as in group II followed by intraperitoneal injection of Amygdalin once a week for 3 weeks). Rats were euthanized and colonic samples were prepared and stained with Hematoxylin & eosin, alcian blue, and immunohistochemical staining using iNOS & COX-2. Colonic mucosa of group II showed mucosal ulceration, hemorrhage, distorted crypts, absent goblet cells, mononuclear lymphocytic infiltration, and a marked increase in both iNOS & COX-2 immunoreactivity in comparison with group I. On the other hand, colonic mucosa of group III exhibited regeneration of the surface epithelium & goblet cells together with a decline in both iNOS & COX-2 immunoreactivity in comparison to group II. In conclusion, amygdalin is a promising therapeutic agent in managing UC.