Background <p>Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) affecting the colon and rectum; patients with IBD are at substantially high risk of colorectal cancer. Probiotics are non-pathogenic microorganisms that have positive effects against pathogenic agents through the stimulation of immune response or direct impact on hepatogens. The current study aimed to evaluate the effect of nisin loaded with chitosan nanogel in the treatment of UC mouse model and the expression of cytokine IL-10/TNF-α.</p> Method <p>The present study was conducted on 16 male Wistar rats. Animals were divided into four control groups: healthy group, UC group created with 2% acetic acid, nisin treatment group, and nisin treatment group loaded with chitosan nanogel. After treatment, colon samples were used for macroscopic and microscopic examinations and evaluation of inflammatory biomarkers. The results were expressed by mean ± standard deviation (<i>P</i> &lt; 0.05). Raw data were analyzed using 7.04 GraphPad program.</p> Results <p>Consumption of nisin loaded in chitosan nanogel caused a significant reduction (<i>P</i> &lt; 0.05) of macroscopic symptoms, and microscopic examination of the nisin group loaded with chitosan nanogel showed mild inflammation, and the results were significantly different from the colitis group. Treatment with loaded nisin significantly (<i>P</i> &lt; 0.05) decreased the level of TNF-α expression compared to the colitis group.</p> Conclusions <p>Nisin loaded in chitosan nanogel can be considered a suitable alternative to current drugs; however, more studies are needed to confirm this hypothesis.</p>