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Considered by some to be the largest metabolic organ of the body, the functional integrity of skeletal muscle is highly dependent on its exceptional plasticity, which is primarily governed by mitochondrial quality control. The signaling axis composed of AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) serves as a critical hub that senses cellular energy status, coordinates mitochondrial biogenesis, regulates muscle fiber type switching, and maintains protein homeostasis. This review systematically delineates the structural functions and synergistic regulatory network of the AMPK/SIRT1/PGC-1α signaling axis. It further elucidates the regulatory roles of this pathway under physiological conditions-such as exercise adaptation and muscle fiber-type transformation-and its dysregulated mechanisms in the pathogenesis of various skeletal muscle disorders, including sarcopenia, disuse atrophy, cachexia, neurogenic atrophy, muscular dystrophy, and type 2 diabetes mellitus-related myopathy. Building on this foundation, this review critically analyzes current multifaceted therapeutic strategies targeting this pathway, encompassing exercise and physical therapy, nutritional and natural products, and small molecule drugs, as well as gene and cell-based therapies. Finally, this review delves into the challenges facing clinical translation in this field, such as the complexity of the signaling network, individual variability, and bioavailability issues. It also proposes future research directions focused on developing precision intervention tools, establishing effective biomarker systems, and exploring combination intervention strategies. Collectively, the AMPK/SIRT1/PGC-1α signaling axis is central to maintaining skeletal muscle metabolic homeostasis, and targeting this pathway provides a robust theoretical foundation and broad application prospects for the prevention and treatment of skeletal muscle-related diseases.