Ulcerative colitis is a chronic inflammatory disease affecting the gastrointestinal tract. In addition to treatments aimed at healing inflammation and tissue damage, addressing redox imbalance and mitochondrial dysfunction is crucial. The aim of the present study is to investigate the effects of Alpha-Lipoic Acid (ALA), either alone or in combination with mesalamine, on oxidative/nitrosative stress, mitochondrial dynamics, and histopathological changes in a rat model of ulcerative colitis. Rats were divided into Control (C), Ulcerative Colitis (UC), Mesalamine (M), ALA, and Mesalamine + Alpha-lipoic acid (M + ALA) groups. Colitis was induced by intrarectal administration of 4% acetic acid. The disease activity index was the highest in the UC group and the lowest in the M + ALA group among the treatment groups. Macroscopic scores in the UC, M, and ALA groups were significantly higher compared to the C group. The oxidative stress index was the highest in the UC group, with significantly elevated levels compared to the C, ALA, and M + ALA groups. The nitrotyrosine level was also highest in the UC group and significantly elevated compared to the C, M, ALA, and M + ALA groups. Dynamin-related protein 1, Mitofusin-2, and PTEN-induced putative kinase 1 proteins showed significant increases in the UC group compared to the C group. In contrast, these protein levels were significantly reduced in the M + ALA group compared to the UC group. Histopathological scoring in the UC group increased, and ALA administration significantly ameliorated these parameters. Our results indicate that ALA has beneficial effects on increased oxidative stress, impaired mitochondrial dynamics, and altered histopathological scores in the rat colitis model.