Following ischemic stroke, energy depletion, mitochondrial depolarization, oxidative stress, and disrupted calcium homeostasis lead to the accumulation of damaged mitochondria, which in turn amplifies neuroinflammation and cell death. As a selective mechanism for eliminating damaged mitochondria, mitophagy contributes to mitochondrial quality control and may represent one of the mechanisms involved in exercise-mediated neuroprotection after ischemic stroke. This review synthesizes evidence on mitophagy in cerebral ischemia and its regulation by exercise. We discuss the ubiquitin-dependent PINK1/Parkin pathway, the receptor-dependent BNIP3L/NIX and FUNDC1 pathways, and their upstream regulation by AMPK/ULK1, SIRT3, Sesn2/AMPK/TFEB, and PGC-1α/FNDC5/irisin signaling. We also compare exercise preconditioning with post-stroke training in terms of initiation time, modality, intensity, and dose. Preclinical evidence indicates that exercise improves neurobehavioral outcomes after cerebral ischemia and enhances mitochondrial respiration, dynamics, and biogenesis. However, direct evidence that exercise protects ischemic brain tissue through mitophagy remains limited. Most studies rely on static markers, including LC3, p62, PINK1, Parkin, and BNIP3L/NIX, which cannot distinguish mitophagy-specific flux or establish causality. The optimal timing, intensity, and dose of exercise also remain undefined. Future studies should integrate mitochondria-targeted flux reporters, genetic interventions, and standardized reporting of exercise parameters using the frequency, intensity, time, type, volume, and progression (FITT-VP) framework to clarify the mechanistic contribution of mitophagy and inform future translational research.
