The maximal strength and power output, fastest contraction speed and strength generation rate of muscles, as well as muscle endurance, are key factors affecting athletic performance. The generation of muscle strength involves a series of biological cascade reactions, starting from excitations in the cerebral cortex to the activation of motor units and excitation-contraction coupling, ultimately leading to muscle activation. The generation and maintenance of muscle strength can be affected by multiple factors, including the imbalance of the internal environment, disruption of neuromodulation, oxidative stress, and inflammatory reactions, as well as the functional disorders during the process of neuroendocrine remodeling induced by disruption of energy metabolic homeostasis and muscle-organ crosstalk mediated by exerkines, eventually leading to exercise-induced fatigue. Appropriate modalities of exercise training and the activation of key targets responsible for the regulation and transcriptional control in exercise metabolism play a crucial protective role in promoting adaptive changes and preventing exercise-induced fatigue. Taking neuroendocrine remodeling, key targets of exercise epigenetics, and specific biomarkers associated with exercise-induced fatigue as entry points, this article systematically reviews the research progress on the molecular mechanisms and intervention approaches involving exercise-induced fatigue, aiming to provide novel insights and theoretical references for early monitoring and reasonable intervention of exercise-induced fatigue.