Background: The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the complex pathology of the virus, which extends beyond respiratory symptoms to include multisystem inflammatory syndrome (MIS). This review explores the role of Acute Vascular Distress Syndrome (AVDS) in the development of MIS in both adults (MIS-A) and children (MIS-C), providing a comprehensive overview of modern research and treatment approaches for severe coronavirus infections. Methods and Materials: This review synthesizes findings from multiple studies and clinical reports to analyze the mechanisms by which SARS-CoV-2 induces AVDS and subsequently MIS. Key materials include molecular and cellular research data, clinical case studies, and treatment protocols. Diagnostic tools such as PCR and serological testing, as well as various biomarkers like neurofilament light chain and galectin-3, are discussed to elucidate their roles in identifying and managing severe COVID-19 cases. Results: The interaction between SARS-CoV-2 and host endothelial cells, mediated by ACE2 receptors, triggers a cascade of inflammatory responses leading to AVDS. This syndrome is characterized by severe endothelial dysfunction, cytokine storms, and mitochondrial distress, which collectively contribute to the pathogenesis of MIS. Clinical evidence indicates that AVDS is a critical factor in the severity of COVID-19, with widespread implications for multiple organ systems, including the central and peripheral nervous systems. Conclusion: Understanding the role of AVDS in MIS development offers valuable insights into the pathophysiology of severe COVID-19. Effective management requires a multifaceted approach, combining antiviral therapies, immunomodulators, and supportive treatments like extracorporeal membrane oxygenation (ECMO). Future research should focus on targeted therapies to mitigate endothelial damage and improve patient outcomes in critical COVID-19 cases.