Friedreich's ataxia (FA), a progressive neurodegenerative disorder, stems from Frataxin (FXN) gene mutations, leading to a deficiency in frataxin, a crucial protein for mitochondrial function and iron–sulfur cluster biogenesis.1 Frataxin loss impacts key regions of the central nervous system (CNS), like the cerebellum and spinal cord, contributing to neurological deficits that can involve destabilization of the actin cytoskeleton and hinder axonal regeneration in affected neurons.2 These underlying mechanisms highlight potential therapeutic avenues, with mitochondrial restoration being a key focus, although the complex issue of tissue-specific iron dysregulation presents challenges for treatment development.3 Notably, PGC-1α, a key regulator of mitochondrial biogenesis, could be diminished in FA, making it a promising therapeutic target.4 However, arctigenin (ATG) activates PGC-1α; its poor solubility and extensive metabolism limit its clinical use.5 Herein, we developed ARC-18, a novel ATG derivative with enhanced pharmacological properties (Supplementary data). ARC-18 effectively restored mitochondrial function by restoring the levels of key proteins involved in mitochondrial dynamics (DRP1, OPA1, and MFN1) and biogenesis/mitophagy (PINK1/Parkin) and respiratory complex activity in cellular and mouse models of FA with frataxin deficiency. Concurrently, ARC-18 improved motor coordination and neuronal pathology in YG8R mice, which was dependent on the activation of PGC-1α. Mechanistically, FXN deficiency suppressed PGC-1α, while ARC-18 treatment restored its expression; this ARC-18 effect was abated by SR-18292 (a PGC-1α inhibitor), confirming pathway dependence.