Abstract Background Impaired gut microbiota leads to pathogenic bacteria infection, pro-inflammatory response and post-weaning diarrhea. Enterotoxigenic Escherichia coli (ETEC) K88 is a major cause of post-weaning diarrhea in weaned piglets. Fermented soybean meal (FSBM) could relieve diarrhea, alleviate inflammatory response, and modulate gut microbiota of weaned piglets. We used ETEC K88-challenged weaned piglet model to investigate the effects of FSBM on the growth performance, inflammatory response and cecal microbiota. Twenty-four crossbred piglets (6.8 ± 0.5 kg; 21 ± 2 days of age) were allotted into 2 treatment fed the diets with or without FSBM (6% at the expense of soybean meal). Six weaned piglets in each diet treatment were challenged by ETEC K88 (1 × 109 CFU/piglets) on day 15. The experimental period lasted for 20 days. Results The ETEC K88 challenge decreased (p