Muscle disuse atrophy is characterized by a significant reduction in skeletal muscle mass and strength, primarily induced by prolonged periods of inactivity and inadequate mechanical stimulus. This condition is frequently encountered in clinical scenarios, especially in cases where patients undergo limb immobilization due to injuries or suffer from spinal cord impairments. The severity of muscle atrophy is often exacerbated by additional factors, such as advancing age and nutritional deficiencies, underscoring the multifaceted nature of this condition. Over the last two decades, significant advancements have been made in understanding the processes that lead to muscle degradation. Insights into the molecular and cellular mechanisms driving muscle catabolism in the absence of regular physical activity have been gained through research utilizing rodent models such as hindlimb unloading and immobilization, denervation, and spinal cord isolation. These experimental models have provided information on the morphological and functional deterioration as well as the extent of understanding of the molecular and cellular processes in response to disuse-induced muscle wasting. Despite these efforts, the therapeutic options for ameliorating muscle disuse atrophy are limited. Resistance training has been identified as the most effective intervention for reversing muscle mass and strength loss, yet it may only be feasible for some patients due to physical limitations or a lack of motivation to engage in intensive exercise routines. In response to these challenges, ongoing research is focused on identifying alternative therapeutic strategies, encompassing both pharmacological and non-pharmacological approaches, aimed at either preventing the onset of muscle atrophy or facilitating recovery following atrophic events. The implications of muscle disuse atrophy extend beyond clinical manifestations, impacting individuals’ quality of life by impairing physical endurance and the capacity to perform daily activities. This chapter aims to offer an exhaustive summary of the various signals, pathways, and breakdown mechanisms implicated in muscle atrophy. Additionally, it will present the latest developments in therapeutic strategies addressing this condition.