The aim of this study was to investigate the effects of stimbiotic (STB), a xylanase and xylo-oligosaccharide complex. A total of 36 male weaned pigs with initial body weights of 8.49 ± 0.10 kg were used in a 3-week experiment. The experiment was conducted in a 2 × 3 factorial arrangement (six replicates/treatment) of treatments consisting of two levels of challenge (challenge and non-challenge) and three levels of STB (0, 0.5, and 1 g/kg diet). Supplementations STB 0.5 g/kg (STB5) and STB 1 g/kg (STB10) improved the G:F (p = 0.04) in piglets challenged with STEC. STB supplementation, which also decreased (p < 0.05) the white blood cells, neutrophils, lymphocytes, and expression levels of tumor necrosis factor-alpha and interleukin-6. Supplementations STB5 and STB10 improved (p < 0.01) the lymphocytes and neutrophils in piglets challenged with STEC on 14 dpi. Additionally, supplementations STB5 and STB10 improved (p < 0.01) the tumor necrosis factor-alpha in piglets challenged with STEC on 3 dpi. Supplementations STB5 and STB10 also improved the villus height-to-crypt depth ratio (p < 0.01) in piglets challenged with STEC. Supplementation with STB reduced (p < 0.05) the expression levels of calprotectin. In conclusion, STB could alleviate a decrease of the performance, immune response, and inflammatory response induced by the STEC challenge.