This chapter examines three critical physiological mechanisms underlying Long COVID fatigue: mitochondrial dysfunction, neurological impacts, and vascular system changes. Through detailed analysis of recent molecular investigations and advanced imaging studies, the chapter illustrates how SARS-CoV-2 infection triggers a complex cascade of cellular disruption, leading to persistent energy deficits. The text explores how viral invasion directly damages mitochondrial structures and sustains dysfunction through oxidative stress and autoimmune responses, supported by emerging biomarker studies. The neurological perspective presents a comprehensive framework of affected brain regions, neurotransmitter alterations, and clinical manifestations, with particular emphasis on brainstem vulnerability and its implications for chronic fatigue. The chapter concludes with an examination of vascular system changes, progressing from endothelial dysfunction through microcirculatory changes to widespread tissue effects. Each section is accompanied by detailed figures illustrating the complex pathways and interconnections between these systems. The chapter synthesizes findings from multiple recent studies published in leading journals, providing insights into potential therapeutic approaches while highlighting the need for multi-targeted interventions due to the complex, interconnected nature of Long COVID fatigue pathophysiology.