Objective Exploring the antidiarrhea effect of new Ershen pills composed of nutmeg koji based on the spleen and kidney yang deficiency diarrhea mouse model. Methods KM mice were randomly divided into normal, model,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, and nutmeg koji groups. The combined modeling method of hydrocortisone + senna leaf was used to establish the diarrhea mouse model with spleen-kidney yang deficiency. General signs and pathological changes of each organ were observed. Various organ indexes, the 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 assessed. 16S rDNA sequencing and data analysis were conducted for fecal microorganisms. Results After modeling, compared with the normal group, the weight and activity of mice in the model group were reduced, the small intestine propulsion rate was significantly increased, the gastric residual rate and organ indexes were significantly decreased, serum GAS, CORT, TSH, and T levels were significantly decreased, MTL, TNF-α, and IL-1β levels were significantly increased, and intestinal flora species diversity was decreased. After administration, the above indexes and symptoms were improved by various degrees in each administration group, and the Ershen pills Ⅱ group was better than Ershen pills Ⅰ, Ershen pills Ⅲ, salt-psoralea, and nutmeg koji groups. Conclusions Combined use of nutmeg koji and salt psoralen has a remarkable effect on diarrhea of spleen-kidney yang deficiency. Fermented nutmeg reduces its toxicity risk and enhances its effect of warming the spleen and preventing diarrhea, which facilitates the development of nutmeg koji.