A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the polymerase gamma (PolG) mutator mouse, harbouring a proofreading‐deficient copy of PolG, exhibits an accelerated aging phenotype, systemic mitochondrial dysfunction, multisystem failure, and reduced lifespan. Studies in primary cells from mitochondrial myopathy patients indicate that inducing mitochondrial biogenesis via over‐expression of PGC‐1α has therapeutic potential. We aimed to delineate if endurance exercise‐mediated induction of PGC‐1α metabolic network can prevent premature aging and systemic decline in PolG mice. At 3‐mo, 36 PolG mice (♀ = ♂) were randomly assigned to a sedentary (SED) or forced‐endurance training (END; 15m/min for 45 min, 3x/week for 5 months) group. In skeletal muscle, END increased nuclear abundance of PGC‐1α (76%) while concomitantly decreasing RIP140 (a negative regulator of PGC‐1α; 33%) nuclear content (P<0.05). END also increased mtDNA copy number (2–3 fold), protein content of respiratory chain subunits (CI‐NUFA9, CII‐subunit 70 kDa, C‐III core 2, and COX‐IV; 2–3 fold), and COX activity (22–120%) in skeletal muscle, lungs, heart, brain, and gonads (P<0.05). These molecular adaptations conferred complete phenotypic protection, reduced multi‐organ pathology, and increased lifespan of PolG mice. We conclude that END training promotes PGC‐1α‐mediated systemic mitochondrial oxidative capacity, contributing to the complete rejuvenation of PolG mice. We propose that END training offers a valuable therapeutic intervention for attenuating and/or reversing mitochondrial abnormalities associated with aging. (Funded by CIHR, and Mr. Warren Lammert and family)