Understanding the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that herpesviruses' infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment – symptoms consistent with ME/CFS and Long COVID. The paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within ECs of ME/CFS patients. This review offers a conceptual advance by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research towards potentially unexplored avenues in understanding and treating this complex syndrome.