<p>Throughout the world-wide COVID-19 pandemic, there has arisen a significant and a sustained public-health issue, whereby a significant proportion of individuals report persistent symptoms, well beyond the acute period of infection. The non-united array of chronic, multisystemic events, such as fatigue, cognitive deficit, respiratory dysfunction, cardiovascular abnormalities, and neuropsychiatric disorders characterize this sequela, which is referred to as LCS. LCS is much more than the starting viral insult, as it causes long-term complications that impact various organ systems. The current review questions the pathophysiological mechanisms of LCS, including scrutinizing the importance of the dysregulation of immunity, the persistence of viral reservoirs, endothelial dysfunction, autonomic imbalance, and mitochondrial injury. We highlight the heterogeneity of the syndrome and the associated diagnostic and treatment difficulties. In addition, we stress the urgency of powerful biomarkers that will be used to diagnose LCS as early as possible and monitor it over time. Present treatment strategies, including pharmacologic therapy (immunomodulators, anticoagulants, antiviral medications, etc.) and non-pharmacologic treatment (rehabilitative programs, etc.) are discussed against the backdrop of recent clinical findings. This review incorporates the recent literature and presents a review of potential treatment options that alleviate symptoms and improve the quality of life of LCS patients. Finally, this integrated synthesis can be used by both clinicians and researchers to gain practical information on the diagnosis, treatment, and future treatment directions of LCS.</p>