Objective: To explore the protective effect of the crude extract of Salsola imbricata against acetic acid-induced inflammatory bowel disease in mice and its mechanism of action. Methods: Ethanolic crude extract of Salsola imbricata was characterized by HPLC. Salsola imbricata extract at different doses was administered and ulcerative colitis was induced by 200 μL, 7.5% acetic acid and macroscopic parameters were evaluated to assess the homeostatic condition of intestinal mucosa along with hematological and biochemical assays. The levels of malondialdehyde, glutathione peroxidase 1, superoxide dismutase, and catalase were determined in colon tissues. Proinflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were quantified by ELISA. The extent of tissue damage was assessed by histological analysis. Results: Phytochemical analysis confirmed the presence of phytochemicals including quercetin, gallic acid, syringic acid, benzoic acid and chlorogenic acid in the crude extract. The crude extract of Salsola imbricata (300 and 500 mg/kg) markedly decreased malondialdehyde and nitric oxide (P<0.01) and increased antioxidant activities of glutathione peroxidase 1 (P<0.001) and superoxide dismutase (P<0.001). Moreover, it decreased the levels of IL-1β, IL-6 and TNF-α significantly (P<0.001) and reduced the damage to the colon mucosa, promoting tissue healing and regeneration. Conclusions: Salsola imbricata extract restores the colonic epithelial layers by maintaining mucosal homeostasis and cell integrity by modulating antioxidant defense system and inflammatory cytokine signaling in ulcerative colitis mice.