Objective: To .study the improving effect of Anemarrhenae Rhizoma-Phellodendri Chinensis Cortex herb pair(Zhi Bai) on cognitive impairment in D-galactose(D-gal) administered mice, and to explore the mechanism of Zhi Bai in improving cognitive impairment through the AMPK/mTOR signaling pathway. Methods: Seventy-five C57BL/6J mice were randomly divided into five groups: the control group, the model group (D-gal 125 mg/kg), the piracetam group (468 mg/kg), the Zhi Bai group (4.5 g/kg), and the mTOR inhibitor group (everolimus, RAD001, 3 mg/kg), with 15 mice in each group. The aging mouse model was established using D-gal, followed by 8 weeks of oral administration of Zhi Bai decoction. Cognitive functions in aging mice were assessed using the Morris water maze and novel object recognition tests. Hippocampal tissue pathology was observed using hematoxylin and eosin (H& E) staining; neuronal and synaptic pathological morphology in the hippocampal region was examined with Nissl and Golgi staining. Hippocampal tissues were collected to determine the levels of adenosine triphosphate (ATP) in the brain. The protein expression levels of ubiquitin-binding protein 62 (P62), Beclin-1 associated with myosin, light chain kinase BCL2 (Beclin-1), synaptophysin (Syn), postsynaptic density protein-95 (PSD-95), AMP-activated protein kinase (AMPK), and mTOR in the hippocampus were detected by Western blot. The gene expression levels of Syn, AMPK, and mTOR in the hippocampus were measured using quantitative real-time PCR (qRT-PCR). Results: Compared to the control group, the model group mice showed significant cognitive impairment in the Morris water maze and novel object recognition tests (P<0.01). In the model group, there was a reduction in cell numbers, loose cell arrangement, and irregular neuronal morphology, a significant decrease in Nissl bodies, and a decrease in dendritic branch and spine density in the hippocampal region. ATP levels, as well as P62, Syn, PSD-95, and mTOR protein expressions in the hippocampus of the model group, were significantly reduced (P<0.01), while Beclin-1 expression was significantly increased (P<0.01). The ratio of pAMPK to AMPK protein content and the expression of AMPK genes were significantly elevated (P<0.01), whereas Syn and mTOR gene expressions were significantly decreased (P<0.01). Compared to the model group, cognitive function was significantly improved in the piracetam and Zhi Bai groups, as evidenced by a significant reduction in the latency period in the Morris water maze test (P<0.01), increased platform crossing numbers and target quadrant dwell time (P<0.01), and a significant increase in the novel object recognition index (P< 0.01). Dendritic spine density in the hippocampal region was significantly increased (P<0.01), and neuronal damage was alleviated to some extent. ATP levels and P62, Syn, PSD-95, and mTOR protein expressions in the hippocampus were significantly increased (P<0.01, P<0.05), Beclin-1 protein expression was significantly reduced (P<0.01), and the ratio of pAMPK to AMPK protein content and AMPK gene expression were significantly decreased (P<0.01, P<0.05), with Syn and mTOR gene expressions significantly elevated (P<0.01). The results for the RAD001 inhibitor group were similar to the model group, but Zhi Bai treatment led to a recalibration of these indicators. Conclusion: Zhi Bai may inhibit excessive autophagy of neurons, enhance synaptic plasticity and improve D-gal-induced cognitive impairment in mice by activating the AMPK/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]