Objective To evaluate the antidiarrheal effect of new ershen pills composed of nutmeg koji instead of bran stewed nutmeg.Method Kunming mice were randomly divided into normal group, model group, Ershen pills Ⅰ (salt psoralen + bran stewed nutmeg), Ershen pills Ⅱ (salt psoralen + nutmeg koji), Ershen pills Ⅲ (salt psoralen + nutmeg raw product), salt psoralen group, and nutmeg koji group. The combined modeling method of "hydrocortisone + senna leaf" was used to establish the diarrhea mouse model with spleen-kidney Yang deficiency. The general signs and pathological changes of each organ were observed. The levels of various organs index, small intestine propulsion rate, gastric residual rate, serum motilin (MTL), gastrin (GAS), adrenal ketone (CORT), thyroid stimulating hormone (TSH), testosterone (T), tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were detected. 16S rDNA sequencing and information analysis were conducted for fecal microorganisms. Results After modeling, compared with normal group, the weight and activity of mice in model group were reduced, small intestine propulsion rate was significantly increased, gastric residual rate and organ index were significantly decreased, serum GAS, CORT, TSH and T levels were significantly decreased, MTL, TNF-α and IL-β levels were significantly increased, and intestinal flora species diversity was decreased. After administration, the above indexes and symptoms were improved in different degrees in each administration group, and Ershen Pills group Ⅱ was better than Ershen Pills group Ⅰ, Ershen Pills group Ⅲ, salt-psoralea and myristoqu groups. Conclusion The combined use of nutmeg koji and salt psoralen has a remarkable effect on the diarrhea of spleen and kidney Yang deficiency. The fermented nutmeg can reduce its toxic risk and enhance its effect of warming spleen and preventing diarrhea, which laid a foundation for the development of nutmeg koji.