Intensive Care Unit-Acquired Weakness (ICU-AW) is a common and severe complication in critically ill patients, characterized by profound and often prolonged muscle weakness. The complexity of its diagnosis and management requires a multidimensional approach that integrates clinical, electrophysiological, and imaging tools. This review focuses on the challenges in diagnosing ICU-AW, emphasizing the limitations of traditional methods such as manual muscle testing and electrophysiological studies, and highlights the emerging role of neuromuscular ultrasound (NMUS) as a promising, non-invasive diagnostic aid. Despite its utility, no gold standard exists for NMUS, making it an evolving area of research. The pathophysiological basis of ICU-AW involves multiple mechanisms, including critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and muscle atrophy due to disuse. Understanding these underlying mechanisms is crucial for advancing diagnostic strategies and informing therapeutic interventions. Recent insights into the molecular and cellular pathways involved, such as the role of oxidative stress, mitochondrial dysfunction, and the ubiquitin-proteasome system, have opened new avenues for targeted therapies. Management of ICU-AW remains challenging, as no specific treatment has been proven fully effective. Current strategies focus on early mobilization, minimizing sedation, and optimizing nutritional support. Emerging therapies targeting molecular pathways involved in muscle degradation are under investigation, highlighting the potential to translate pathophysiological understanding into therapeutic innovations. This review underscores the need for ongoing research to establish standardized diagnostic protocols and develop targeted treatments for ICU-AW.