Background: Salmonella Typhimurium causes gastroenteritis which is characterized by diarrhea. Nowadays, instead of using antibacterial therapies to treat colitis, there is a growing interest in alternative natural products with antibacterial or anti-inflammatory properties. The aim of this study was to investigate the effects of Hyssopus officinalis (Hyssop) and Medicago sativa (Alfalfa), alone and in combination, on salmonella-induced colitis in mice. Methods and results:Graded doses of 50% ethanolic extracts (25, 50, and 75 mg/kg) for 8 days, showed 50 mg/kg for Hyssop and 75 mg/kg for Alfalfa as an optimal effective dose against Salmonella induced colonic damage score which this dosage was further studies in salmonella-induced colitis for other parameters. Our data showed administration of extracts, not only reduced Lipid Peroxidation, myeloperoxidase activity, and nitric oxide levels but also inhibited decreasing of total antioxidant capacity in the colitis group. Also, following oral administration, the extracts had a significant reduction in pro-inflammatory mediators including interleukin-1β and tumor necrosis factor-α, which had better results in the Mix group. Moreover, the Hyssop and Mix group decreased the histological score and Cox-2 mRNA expression, while Nrf-2 gene expression in the treatment groups did not show a significant change compared to the colitis group. Conclusions:In conclusion, Oral Hyssop and Alfalfa extracts, alone and in combination, alleviate the symptoms, oxidative stress, and inflammation of salmonella-induced colitis, and combination therapy with Hyssopus officinalis and Medicago sativa may provide a promising dietary approach for the management of acute bacterial colitis.