This study investigates the effects of soybean meal fermented by Enterococcus faecium as a replacement for soybean meal on growth performance, apparent total tract digestibility, blood profile and gut microbiota of weaned pigs. Eighty piglets (weaned at 21 days) [(Landrace × Yorkshire) × Duroc] with average body weight of 6.52 ± 0.59 kg) were selected and assigned to 4 treatments/4 replicate pens (3 barrows and 2 gilts). The four diets (SBM, 3, 6 and 9% FSBM) were formulated using fermented soybean meal to replace 0, 3, 6 and 9% of soybean meal, respectively. The trial lasted for 42 days phase 1, 2 and 3. Result showed that supplemental FSBM increased (P < 0.05) the body weight gain (BWG) of piglets at day 7, 21 and 42 and ADG at days 1–7, 8–21, 22–42 and 1–42, and ADFI at days 8–21, 22–42 and 1–42 and G: F at days 1–7, 8–21 and 1–42, and crude protein, dry matter, and gross energy digestibility at day 42, and lowered (P < 0.05) diarrhea at days 1–21 and 22–42. The concentration of glucose levels, WBC, RBC, and lymphocytes were increased while, concentration of BUN level in the serum was lowered in the FSBM treatment compared to the SBM group (P < 0.05). Microbiota sequencing found that FSBM supplementation increased the microbial Shannon, Simpsons and Chao indexs, (P < 0.05) and the abundances of the phylum Firmicutes, and genera prevotella, Lactobacillus, Lachnospiraceae and Lachnoclostridium (P < 0.05), lower in the abundances of the phylum bacteroidetes, Proteobacteria, genera Escherichia-Shigella, Clostridium sensu stricto1, Bacteroides and Parabacteroides (P < 0.05). Overall, FSBM replacing SBM improved the growth performance, apparent total tract digestibility, and blood profiles; perhaps via altering the faecal microbiota and its metabolites in weaned pigs. The present study provides theoretical support for applying FSBM at 6–9% to promote immune characteristics and regulate intestinal health in weaning piglets.