Background <p> Sepsis-associated muscle wasting (SAMW) is a devastating complication affecting critically ill patients, characterized by rapid skeletal muscle loss and persistent weakness extending beyond hospital discharge, significantly impairing quality of life and increasing mortality. Despite its clinical importance, effective therapies remain limited due to multifactorial pathogenesis and substantial translational gaps between preclinical research and human disease.</p> Summary of Content <p> This review synthesizes the complex pathophysiology of SAMW, emphasizing the interplay between inflammatory signaling cascades (NF-κB, JAK/STAT, p38MAPK), mitochondrial dysfunction, programmed cell death pathways (apoptosis, pyroptosis), oxidative stress, and gut microbiota dysbiosis. We critically evaluate emerging therapeutic strategies, including anti-inflammatory/antioxidant agents, immunomodulatory therapies, growth factors, exercise interventions, mitochondrial protectants, and Traditional Chinese Medicine (TCM). Notably, TCM is highlighted for its unique multi-target potential—herbal compounds like astragaloside IV and acupuncture simultaneously modulate inflammation, promote protein synthesis, and improve mitochondrial function, aligning with SAMW's complex biology. However, significant challenges persist: preclinical models inadequately replicate human sepsis pathophysiology, TCM formulations suffer from standardization deficits and lack rigorous clinical validation, and ICU implementation barriers hinder therapeutic deployment.</p> Conclusion <p>Future progress requires integrated multi-omics approaches to elucidate pathway interactions, humanized experimental models to bridge translational gaps, and precision medicine frameworks incorporating biomarker-guided interventions. Realizing TCM's therapeutic potential demands standardized extraction methods, robust clinical trials, and mechanistic validation to establish its role in evidence-based SAMW management.</p> Graphical Abstract <p></p>