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The COVID-19 pandemic has contributed to more than 7 million deaths globally and has triggered a variety of postacute sequelae, now commonly referred to as long COVID, in millions more. Early efforts during the pandemic resulted in several therapies to mitigate the severity and mortality of acute COVID-19. However, despite effective therapies and accumulated immunity through vaccination and natural infection reducing disease severity, COVID-19 continues to contribute to hospitalizations and mortality. Long COVID encompasses several distinct yet overlapping clinical syndromes, and evidence suggests that these manifestations are mediated by numerous underlying mechanisms. There are currently no approved therapies for the treatment of long COVID, driven in part by its heterogeneity in presentation and etiology. This review will outline the current guidelines for treating acute COVID-19 and summarize information on the mechanistic rationale behind various published and ongoing clinical trials investigating potential long COVID therapeutic agents.