ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by a complex pathogenesis that includes Aβ deposition, abnormal phosphorylation of tau protein, chronic neuroinflammation, and mitochondrial dysfunction. In traditional medicine, ginseng is revered as the 'king of herbs'. Ginseng has the effects of greatly tonifying vital energy, strengthening the spleen and benefiting the lungs, generating fluids and nourishing the blood, and calming the mind while enhancing intelligence. Ginsenoside Rg1 (Rg1) is a well-defined major active component found in ginseng, known for its relatively high content. It has been demonstrated to exhibit neuroprotective effects in both in vivo and in vitro models, capable of ameliorating Aβ and tau pathology, regulating synaptic function, and reducing inflammation, oxidative stress, and apoptosis. However, the potential of Rg1 to improve AD pathology through the regulation of mitochondrial dynamics is still uncertain. AIM OF THE STUDY: Despite the active research efforts on drugs for AD, the currently available anti-AD medications can only slow disease progression and manage symptoms, yet unable to provide a cure for AD. Furthermore, some anti-AD drugs failed phase III and IV clinical trials due to significant side effects. Therefore, there is an urgent need to further investigate the pathogenesis of AD, to identify new therapeutic targets, and to explore more effective therapies. The aim of this study is to evaluate the potential therapeutic effects of Rg1 on APP/PS1 double transgenic mice and Aβ MATERIALS AND METHODS: This study investigates the effects of Rg1 in treating AD on APP/PS1 double transgenic mice and Aβ RESULTS: The findings suggest that after 28 days of Rg1 treatment, cognitive dysfunction in APP/PS1 mice was improved. Pathological and immunohistochemical analyses demonstrated that Rg1 treatment significantly reduced Aβ deposition and neuronal loss. Rg1 can improve synaptic dysfunction and mitochondrial function in APP/PS1 mice. Rg1 activated AMPK, enhanced p-AMPK expression, inhibited Drp1, and reduced p-Drp1 levels, which led to increased expression of OPA1, Mfn1, and Mfn2, thereby inhibiting mitochondrial fission and facilitating mitochondrial fusion. Additionally, Rg1 effectively reversed the decrease in mitochondrial membrane potential (MMP) and the increase in ROS production induced by Aβ CONCLUSION: Our research provides evidence for the neuroprotective mechanisms of Rg1 in AD models. Rg1 modulates mitochondrial dynamics through the AMPK/Drp1 signaling pathway, thereby reducing synaptic and mitochondrial dysfunction in APP/PS1 mice and AD cell models.