Abstract: With the acceleration of global aging, the disease burden of Alzheimer’s disease(AD) continues to rise. However, current therapy remains limited to symptomatic relief, and curative strategies that directly target the core pathological mechanisms are still lacking. Mitophagy, a critical process for clearing damaged mitochondria and maintaining cerebral energy homeostasis, has been confirmed to have its dysfunction as one of the core driving factors in the pathological progression of AD. This paper first elucidated the interactive mechanisms among Aβ deposition, Tau hyperphosphorylation, and impaired mitophagy in AD. Followed by a systematic review of therapeutic interventions targeting mitophagy in AD. These included direct activation of mitophagy via the PINK1/Parkin pathway and receptor-mediated pathways, as well as indirect promotion through small molecules, natural products, and non-pharmaceutical therapies that indirectly promote mitophagy by regulating upstream nodes, restoring mitochondrial morphology, maintaining mitochondrial homeostasis, and improving lysosomal function. It further reviewed research progress on novel nanomedicines and biologics with blood-brain barrier penetration advantages. Finally, it summarized current research bottlenecks and outlines prospects for the clinical translation of AD drugs targeting mitophagy, providing new insights for developing effective AD prevention and treatment strategies.