Long COVID has a multifactorial nature with multiple pathophysiological factors at play.Viral factors, host factors (including systemic inflammation, and metabolic, endocrine, and endothelial dysfunction) and downstream impacts (tissue damage from the initial infection, hypoxia, dysbiosis, and autonomic nervous system dysfunction) are key elements underpinning the condition.Various factors culminate in the long-term persistence of the disorder (i.e., a thrombotic endothelialitis characterized by endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots).We suggest a multipronged treatment agenda for Long COVID treatment trials, incorporating drugs targeting all potential mechanisms, including viral persistence, autoimmunity, immune dysregulation, and gut dysbiosis; with endothelialitis and coagulation abnormalities as two priorities. Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation, immune dysregulation, and autoimmunity); and downstream impacts (tissue damage from the initial infection, tissue hypoxia, host dysbiosis, and autonomic nervous system dysfunction). These mechanisms culminate in the long-term persistence of the disorder characterized by a thrombotic endothelialitis, endothelial inflammation, hyperactivated platelets, and fibrinaloid microclots. These abnormalities of blood vessels and coagulation affect every organ system and represent a unifying pathway for the various symptoms of Long COVID.