Post-COVID-19 fatigue emerges as a complex condition involving interrelated central, peripheral, and psychological mechanisms. This chapter examines how SARS-CoV-2 affects multiple systems through distinct but interconnected pathways. Central mechanisms involve viral neuroinvasion through neural, hematogenous, and lymphatic routes, leading to neuroinflammation, neurotransmitter disruption, and structural brain changes. Psychological factors encompass both direct viral-mediated effects and indirect psychosocial impacts, creating a self-perpetuating cycle of fatigue and distress. Peripheral mechanisms include musculoskeletal dysfunction, metabolic alterations, and systemic inflammation, contributing to ongoing fatigue symptoms. The chapter emphasizes the conditional dependency of these mechanisms on task demands, environmental conditions, and individual characteristics. This multifaceted nature of post-COVID-19 fatigue necessitates comprehensive assessment approaches combining various diagnostic techniques, including neuroimaging, neuropsychological testing, and electromyography. Understanding these complex interactions is crucial for developing effective, personalized treatment strategies that address multiple contributing factors simultaneously. Future research directions should focus on integrated assessment approaches to better understand how these various factors interact and evolve over time, ultimately leading to more effective interventions for this challenging condition.