This chapter presents an advanced systems-level analysis of Long COVID fatigue, focusing on the integration of multiple biological mechanisms and their associated biomarkers. Through detailed examination of recent research, the text illustrates how immune, vascular, mitochondrial, and neurological systems interact and amplify each other’s effects, creating self-perpetuating cycles of dysfunction. The chapter builds upon earlier foundational models by elaborating specific molecular and cellular mechanisms underlying these interactions, with particular emphasis on how persistent immune activation serves as a primary driver of ongoing symptoms. The text includes two comprehensive figures: one depicting the interconnected mechanisms underlying Long COVID fatigue and another presenting a systematic overview of key biomarkers and their correlations with clinical manifestations. The biomarker analysis reveals significant associations between specific molecular markers and symptom severity, particularly in inflammatory, immune, and mitochondrial parameters. Through this integrated perspective, the chapter demonstrates the rationale for multi-targeted therapeutic approaches and provides a molecular signature of the condition. This work synthesizes findings from multiple recent studies published in leading journals, offering a comprehensive framework for understanding both the complexity of Long COVID fatigue and potential therapeutic strategies.