To explore efficacy of probiotics combined with donepezil in the treatment of mild and moderate Alzheimer's disease (AD). Methods: Sixty-six AD patients were randomly divided into group A (donepezil tablets + Bifidobacterium triple viable capsules) and group B (donepezil tablets + starch capsules). After 12 weeks of treatment, the efficacy was evaluated, including cognitive function score, inflammatory factors, intestinal flora, and incidence of adverse reactions. Results: After treatment, the mini-mental state examination (MMSE) score and activities of daily living (ADL) score of both groups improved compared with before treatment (P<0.05); the MMSE score of group A was significantly higher than that of group B (P<0.05), but the difference in ADL score was not statistically significant. After treatment, serum levels of inflammatory factors such as IL-1β, IL-6, TNF-α, and CRP were significantly lower in both groups than before treatment (P< 0.05), although the reduction in levels of IL-1β, IL-6, and TNF-α was more pronounced in group A than in group B (P<0.05); the difference in CRP between the groups was not statistically significant (P>0.05). Comparison of the distribution of bacterial species among the intestinal flora groups showed that at the portal level after treatment, Firmicutes, Bacteroides, Proteobacteria, and Actinomycetes were predominant in each group. After treatment, the abundance of Firmicutes was significantly higher in group A compared to group B (P<0.05). Clostridium in group B was significantly reduced compared with that before treatment (P<0.05). In group A, Blautia and Burkholderia were significantly decreased compared with before treatment (P<0.05), while Roseburia and Lactobacillus were significantly increased (P<0.05), and Bifidobacteria were also slightly increased. After treatment, the relative abundance of Lactobacillus, Clostridium, Coprococcus, Ruminococcus, Megomonas, and Suttelia was higher in group A (P<0.05). Correlation analysis found that the inflammatory factor was negatively correlated with butyric acid-producing bacteria such as Roseburia, Oscillospira, and Anaerostipes and positively correlated with harmful bacteria such as Burkholderia and Turicibacter. A comparison of intestinal flora group diversity showed no significant change in α diversity and β diversity. Conclusion: Probiotics combined with donepezil in the treatment of patients with mild to moderate AD offers enhanced benefits and good safety.