Brachyspira hyodysenteriae is the causative agent of swine dysentery and induces a characteristic mucosal inflammation resulting in pronounced typhlocolitis in swine and mice. Hypoxis hemerocallidea corm (African potato) is a traditional medicine in southern Africa. An African potato methanolic extract (APME) and one of its major constituents, hypoxoside, have been shown in vitro to possess an anti-inflammatory property. The aim of this study is to evaluate the ability of APME to prevent or ameliorate B. hyodysenteriae-induced typhlocolitis. Mice were orally treated with APME for seven days prior to B. hyodysenteriae infection and the treatments continued daily for seven days postinfection (DPI). At the termination of the experiment, weight loss, gross and histological lesions, myeloperoxidase (MPO) activity, and intestinal epithelial proliferation were evaluated. In addition, the protein level of activated p65 subunit of nuclear factor-kappaB (NF-kappaB) and mRNA expression of NF-kappaB-associated genes were also measured. APME treatment significantly (P < 0.05) reduced weight loss, the severity of typhlocolitis, mucosal MPO activity and intestinal epithelial proliferation subsequent to B. hyodysenteriae infection. Mucosal protein levels of active p65 and expression levels of NF-kappaB-associated genes following B. hyodysenteriae infection were also decreased by the oral treatment with APME. In conclusion, prophylactic treatment with APME ameliorated B. hyodysenteriae-induced typhlocolitis, suggesting H. hemerocallidea corm methanolic extract may have potential for ameliorating enteropathies that are mediated by overactive host inflammatory processes.