This comprehensive review elucidates the intricate, multifactorial pathophysiology underpinning post-stroke skeletal muscle atrophy, a detrimental complication impacting patient outcomes. Post-stroke complications including dysphagia, malabsorption, and inadequate protein intake precipitate a catabolic state, exacerbating muscle wasting. The dearth of essential amino acids perpetuates proteolysis over protein synthesis, highlighting the importance of nutritional interventions. Immobility-induced disuse atrophy and dysregulation of anabolic pathways, notably IGF/Akt/PI3K, favor proteolysis, disrupting muscle protein homeostasis. Proteolytic systems including the ubiquitin-proteasome pathway and autophagy play central roles. Moreover, transcriptomic alterations, insulin resistance, autonomic dysregulation, inflammation, oxidative stress, and dysregulated microRNAs contribute to reduced muscle mass post-stroke. Notably, matrix metalloproteinases’ (MMPs) implication unveils potential therapeutic avenues via MMP inhibition. Unraveling this complex pathophysiological interplay is crucial for developing multi-modal interventions to manage post-stroke muscle atrophy effectively.