The present study was performed to investigate whether dietary fermented soybean meal (FSBM) inclusion could improve growth performance and ameliorate diarrhea via improving ileal barrier function in weaned piglets challenged by enterotoxigenic Escherichia coli (ETEC) K88, and further analyze the potential roles for inflammatory response and epithelium apoptosis. A total of 32 crossbred barrows (Duroc × Landrace × Large White), 21 ± 2 day of age, and initial body weight of 6.86 ± 0.54 kg) were assigned to 2 diets (basal diet with or without FSBM, 60 g/kg at the expense of soybean meal) and subsequently challenged or not with ETEC K88 (5 × 1010 CFU/piglets) on day 15 of experiment in a 2 × 2 factorial arrangement of treatments. The results showed that weaned piglets fed FSBM had a tendency for greater average daily gain (ADG) compared to piglets fed SBM during day 1–14 (P = 0.081). After ETEC K88 challenge, the challenged piglets had higher (P