The effects of β-mannanase supplementation in metabolizable energy (ME)-reduced diets containing xylanase-phytase were investigated on performance, fecal score, carcass attributes, blood profile, apparent total tract digestibility (ATTD), digesta passage rate, and fecal microbiome in grower pigs (n = 40, 26.09 ± 0.96 kg) randomly assigned within 4 treatments: a control diet containing isolated phytase and xylanase valued at 40 kcal of ME/kg (CD0), CD0 + β-mannanase (0.3 g/kg valued at 30 kcal of ME/kg) (CD70), CD0 + β-mannanase (0.3 g/kg valued at 45 kcal of ME/kg) (CD85), and CD0 + β-mannanase (0.3 g/kg valued at 60 kcal of ME/kg) (CD100). Performance was supported. Pigs with CD100 had lower serum IL-1β concentration, and lower IL-10 was observed in pigs on CD0 than those fed β-mannanase. Greater ATTD was evidenced in animals fed CD85 or CD100. Pigs with CD85 had higher alpha diversity richness but lower Firmicutes:Bacteroidota ratio. Acidaminococcaceae and Ruminococcaceae were more abundant in pigs fed CD0, but lower for Christensenellaceae NSJ-63 and NSJ-63 sp014384805. Pigs in CD85 showed higher abundance of Bacteroidaceae and Prevotella, and lower of Streptococcaceae and Streptococcus. In conclusion, supplementation of β-mannanase in diets containing xylanase-phytase saved 85 kcal of ME/kg by supporting performance, improving nutrient digestibility and fecal microbiome in grower pigs.