Background <p>Colitis is a chronic inflammatory condition characterized by significant tissue damage and oxidative stress. Cirsimaritin, a natural dimethoxyflavone, has potential therapeutic effects, but its efficacy in treating colitis and modulating inflammation, oxidative stress, apoptosis, and histological damage remains to be fully explored.</p> Methods <p>In this study, colitis was induced in experimental models to evaluate the pathophysiological changes. We assessed the capacity of total antioxidant (TAC), activities of superoxide dismutase (SOD) and catalase (CAT), levels of oxidative stress markers (Malondialdehyde [MDA] and Nitric Oxide [NO]), and the gene expression of key inflammatory and apoptotic markers (NF-κB, IL-6, TNF-α, iNOS, IL-1β, TLR4, Bax, Bcl-2, Caspase-3, and Caspase-8). The therapeutic effects of cirsimaritin were analyzed through its ability to modulate these biomarkers and histopathological damage.</p> Results <p>The occurrence of experimental colitis produced remarkable decreases in the activities of TAC, SOD, and CAT (<i>p</i> &lt;.05) and elevation of oxidative stress markers (levels of MDA and NO <i>p</i> &lt;.01). The expression of inflammatory and apoptotic genes was significantly increased (<i>p</i> &lt;.001 for TNF-α, IL-6, TLR4, IL-1β, iNOS, NF-κB; <i>p</i> &lt;.05 for Bax, Caspase-3, and Caspase-8). Cirsimaritin treatment was able to effectively alleviate these changes, decreasing levels of inflammatory cytokines and oxidative stress markers (<i>p</i> &lt;.01) and improving TAC and antioxidant enzyme activities (<i>p</i> &lt;.05); furthermore, cirsimaritin treatment was able to down-regulate apoptotic gene expression (<i>p</i> &lt;.05). The histopathological assessment revealed improved tissue architecture in cirsimaritin-treated groups.</p> Conclusion <p>Cirsimaritin ameliorates colitis by inhibiting inflammation, oxidative damage, and apoptosis in the colon, suggesting its possible therapeutic use.</p>