This comprehensive chapter explores the complex pathophysiological mechanisms underlying fatigue in Long COVID through an integrated analysis of multiple biological systems. The text details how chronic inflammation, immune dysregulation, mitochondrial dysfunction, and vascular abnormalities interact to create a persistent state of fatigue in Long COVID patients. Drawing from numerous high-profile studies published in leading journals, the chapter presents evidence of sustained inflammatory cascades triggered by the initial SARS-CoV-2 infection, leading to long-term cellular and systemic dysfunction. The authors pay particular attention to the role of microglial activation and autoimmune responses, supported by transmission electron microscopy findings showing mitochondrial structural abnormalities and elevated inflammatory markers. The chapter includes detailed illustrations mapping the progression of immune responses through initial, persistent, and chronic phases, emphasizing the self-perpetuating nature of these pathological processes. The text synthesizes findings from multiple large-scale studies and meta-analyses, providing a thorough examination of how various biological systems contribute to the manifestation and maintenance of Long COVID fatigue. This work highlights the challenges in treating Long COVID fatigue due to its complex, multi-system nature and suggests that effective interventions may need to target multiple pathophysiological pathways simultaneously.