BACKGROUND: As a persistent gastrointestinal disorder, irritable bowel syndrome (IBS) influences the gut-brain connection, leading to abdominal pain and altered bowel irregularities. Baicalein, a flavonoid extracted from Scutellaria baicalensis, is frequently utilized in anti-inflammatory treatments. This study aimed to explore baicalein's effectiveness in mitigating IBS symptoms triggered by both chronic and acute stress (CAS) and to uncover its fundamental mechanisms. METHODS: Sprague-Dawley rats were employed to develop an IBS rat model by inducing CAS for five weeks. Each rat was randomly allocated to one of four experimental groups: model (M), low-dose baicalein (L), high-dose baicalein (H), and control (C). Baicalein was orally administered throughout the experiment. Behavioral assessments were conducted, including forced swimming, marble-burying, intestinal motility, and visceral sensitivity tests. Colonic tissues were collected for histopathological examination, evaluation of oxidative stress (MDA and SOD levels), and analysis of inflammatory cytokines, and ODC1/NF-kappaB pathway activation using Western blot assay, ELISA, and immunofluorescence. RESULTS: Baicalein treatment notably ameliorated IBS-like symptoms, such as fecal pellet output and AWR scores, by alleviating stress-induced behavioral changes. Baicalein bolstered antioxidant defenses through boosting SOD activity and lowering MDA levels. Moreover, baicalein inhibited inflammatory responses, targeting IL-6, IL-1beta, and TNF-alpha, while suppressing the expression of ODC1 and restraining NF-kappaB p65 phosphorylation within the colon. These results indicate that baicalein modulates oxidative stress and inflammation in CAS-associated IBS. CONCLUSION: Baicalein demonstrates protection against CAS-induced IBS by diminishing intestinal inflammation, oxidative damage, and visceral hypersensitivity via suppression of the ODC1/NF-kappaB pathway. These findings underscore baicalein's potential as a therapeutic approach for IBS.