Background: Alzheimer's disease (AD) has gradually increased as society has aged and is now a serious social problem. In the clinical treatment of AD, patients show improvement in cognitive function after treatment with the traditional Chinese medicine compound, Yizhi Sheng Hui (YZSH) decoction. This study systematically investigates the effect and pharmacology of the YZSH decoction on AD. Methods: In this study, 24 SAMP8 AD model mice were randomly divided into three groups: an untreated control group, a group treated with the YZSH decoction, and a positive control group treated with donepezil hydrochloride. Eight SAMR1 mice were placed in the normal control group. A Morris water maze test and a step-down test were conducted at 8 and 13 weeks after continuous intragastric administration of the two drugs. After 13 weeks of administration, the hippocampal expression of A beta 1-42 and tau protein were measured. Results: There was no change in the latent period duration and the number of platform crossings in each group after 8 weeks of administration, but after 13 weeks of administration, the latent period of the treatment group and the positive control group were significantly shorter than the untreated control group. Initially, the SAMP8 mice showed a lower spatial exploration ability than the SAMR1 mice. However, after 13 weeks of administration, the treatment group and the control group exhibited a better exploration ability. Compared with the SAMR1 mice, the on-stage evasion time and step-down errors significantly increased in the untreated group. Compared with the untreated group, mice in the treatment group and the positive control group showed a shorter latent period after 8 weeks of administration, and the on-stage evasion time for both groups was significantly reduced after 13 weeks of administration. The treatment group showed fewer instances of electric shock. Hippocampal expression of A beta 1-42 was high in the untreated group, was much lower in the positive control group, and no A beta 1-42 expression was observed in the treatment group. Conclusions: The YZSH decoction improved the learning and memory of mice with AD, related to the inhibition of A beta 1-42 expression.