Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.