Ulcerative colitis (UC) can cause a variety of complications, ranging from colon damage to colorectal cancer. The cause of UC, as well as successful treatment options, remain a mystery. The mechanisms behind the coloprotective benefits of Hyphaena thebaica (H. thebaica) and Lactobacillus, as well as their combined therapy on dextran sodium sulphate (DSS)-induced colitis in rats, are the subject of this study. The experimental panel included seven groups of rats; normal control, negative plus H. thebaica, negative plus Lactobacillus, UC diseased rats, H. thebaica treated, Lactobacillus treated, and combination of H. thebaica and Lactobacillus treated. Clinical evaluation of UC and both macroscopic and microscopic examination scoring was also done. Colonic oxidants/antioxidant stress biomarkers; malondialdehyde (MDA), glutathione (GSH), catalase, myeloperoxidase activity, and superoxide dismutase (SOD) activity were assessed. Colon Nrf2, HO-1 contents, TNF-α as well as caspase and Bax proteins was evaluated. H. thebaica in conjunction with Lactobacillus, greatly reduced dextran sodium sulphate-induced colon injury (DSS). In addition, the tested drugs dramatically decreased DSS-induced oxidative, inflammatory, and apoptotic activities.