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Leber hereditary optic neuropathy (LHON) is a typical mitochondrial genetic optic neuropathy predominantly affecting retinal ganglion cells and leading to irreversible visual damage. Although a single primary mitochondrial DNA (mtDNA) mutation provides the basis for the disease, it cannot fully explain its incomplete penetrance, male predominance, and clinical heterogeneity. Based on familial genetic analysis and functional studies, this review summarizes the "triple-hit" pathogenic mechanism of LHON. The first hit consists of primary mtDNA mutations, such as m.11778G>A, m.14484T>C, and m.3460G>A, which primarily impair respiratory chain complex Ⅰ function and weaken mitochondrial energy metabolism. The second hit involves mtDNA modifier variants, mtDNA haplogroup backgrounds, and nuclear modifier gene variants, which lower the threshold for disease onset and affect the penetrance in primary mtDNA mutation carriers. The third hit consists of non-genetic triggers, including exogenous exposures (such as smoking, alcohol consumption, and exposure to mitochondrial-toxic drugs) and endogenous physiological abnormalities (such as sex hormone-related differences in mitochondrial protection), which further weaken mitochondrial compensatory capacity and ultimately precipitate retinal ganglion cell damage. This review provides an integrated framework for understanding the pathogenic mechanism of LHON, aiming to serve as a reference for the screening of high-risk individuals, genetic counseling, risk prediction, and mechanism-driven clinical research of LHON.