Background & Objective: Inflammatory bowel diseases (IBDs) represent serious chronic auto-inflammatory conditions, affecting the alimentary tract. The beneficial effect of dexpanthenol has been observed on some inflammatory conditions. Here, the therapeutic potential of combined dexpanthenol and prednisolone in alleviating the symptoms of the animal model of IBD was investigated. Materials & Methods: Luminal instillation of 4 acetic acid (2 ml for each rat) was used to induce IBD. Rats in the treatment groups received dexpanthenol (500 mg/kg), prednisolone (2 mg/kg), or a combination of both (half doses of each drug) by oral gavage for 11 consecutive days. Results: Dexpanthenol could regress the clinical scores of the IBD model more than prednisolone. More importantly, combination therapy with half doses of dexpanthenol and prednisolone caused more considerable improvement in the disease activity index (DAI) compared to IBD rats received monotherapy. Both monotherapies promoted a remarkable decrease in the messenger RNA (mRNA) expression of NF-κBp65, as well as the levels of interleukin 6 (IL-6) and TNF-α activity in the inflamed colon. Dexpanthenol could regress the intensity of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) in the inflamed colon more than prednisolone. More importantly, our results demonstrated that combination therapy resulted in a much more prominent decrease in the level of TNF-α and NF-κBp65, as well as the level of superoxide dismutase (SOD) and total gut protein content, than monotherapy. Conversely, combination therapy resulted in a much more pronounced decrease in NO and MDA levels than those recorded in IBD rats received individual treatment. Finally, the mRNA level of IκBα did not show any remarkable discrepancy between the experimental groups. Conclusion: The combination of dexpanthenol and prednisolone could be used as a promising strategy to alleviate the signs of IBD.