Background: The uncertainty of the etiologic factors of inflammatory bowel disease (IBD) and the failure of current treatment strategies to control'many cases of IBD make a strong stimulus to find out a new relatively safe and effective modality of treatment. Recent studies pointed to the important role of free oxygen radicals in the pathogenesis of IBD both in animal models of induced colitis and in human beings. Aims: to explore the possible beneficial prophylactic and therapeutic effect of monotherapy with oral zinc sulfate, curcumin, black cumin oil for induced colitis in rabbits in comparison with prednisolone, the current routine therapy for IBD. Materials and Methods: Colitis was induced in male rabbits by rectal administration of 5% acetic acid-30% ethanol (model 1), or 2% acetic acid (model 2). Animals in different groups were orally administered distilled water (control), prednisolone (2 mg/kg/day), zinc sulfate (50 mg/kg/ day), or curcumin (50 mg/kg/day). Black cumin oil (0.2 ml/kg/day) was administered orally for rabbits in model 2 only. The effects were observed as changes in bod}' weight, colon segment weight, gross histological score, microscopical score. Plasma zinc and copper concentrations were measured in control and zinc sulfate groups in both models Results: In model 1, 5% acetic acid- 30% ethanol induced severe gross and microscopical damage in colon with marked increments in weight of colonic segment. Gross and microscopical scores of each of zinc sulfate and curcumin groups were not significantly different from that of the control and of the prednisolone groups (p >0.05). In model 2, 2% acetic acid induced a less severe form of inflammation in colon; yet, it had a marked effect in reducing the body weight of rabbits and with evident gross and microscopical damage in colon. Black cumin oil and prednisolone treatment reduced the loss of body weight of rabbits in comparison to the control group. The means gross histological score were apparently lowered in all treatment groups (including prednisolone group), but these reductions were significant only for prednisolone, zinc sulfate and black cumin groups (p < 0.05). The mean microscopical score was apparently lowered in all treatment groups but these reductions were significant only for prednisolone, and zinc sulfate groups (p < 0.05). The effects of zinc sulfate, curcumin, and black cumin oil in regards to colonic segment weight, gross histological score, and microscopical score were comparable to those of prednisolone (p > 0.05). In both models (1 and 2), a significant decrement in post induction mean plasma zinc level was detected (p < 0.05); however, such decrement could be corrected by zinc sulfate therapy. Conclusions: Acetic acid (2%)-induced colitis in rabbits is preferred for testing the anti-inflammatory effectiveness of new therapeutic modalities. Each of zinc sulfate and black cumin oil has a valid prophylactic activity against acetic acid-induced colitis in rabbits. Curcumin has an accepted anti-inflammatory activity against acetic acid -induced colitis in rabbits. Decrement in plasma zinc levels occurs in all studied animals in acetic acid (5%) - Ethanol (30%) and in acetic acid (2%)-induced colitis, pointing to the importance of zinc supplementation in cases of colitis.