SARS-CoV-2 infection triggers activation of the complement cascade through direct interaction with viral components or virus-specific antibodies, typically resolving once the infection is cleared. However, in patients with long COVID, this activation may persist, potentially contributing to ongoing symptoms. Several proposed mechanisms of long COVID can directly activate the complement system. For example, antiherpesvirus antibodies, likely the result of herpesvirus reactivation, or autoantibodies may drive activation via the classical pathway. Insertion of TCC in the endothelial cell wall causes activation and cell damage, causing the release of TSP1 and vWF. TSP1 promotes formation of monocyte-platelet aggregates, while vWF release — coupled with reduced levels of ADAMTS13, the metalloproteinase responsible for processing vWF multimers — leads to the accumulation of large or ultralarge vWF multimers on the endothelial surface. This, in turn, promotes platelet recruitment and thrombus formation. Additionally, vWF multimers on the endothelium, along with properdin and P selectin on activated platelets, can trap C3b, fueling complement activation via the amplification loop of the alternative pathway. Uncontrolled complement activation in the vasculature leads to red blood cell lysis, causing the release of heme and activation of the alternative pathway. Finally, tissue damage resulting from acute COVID-19, autoimmunity, or viral antigen reservoirs may all contribute to the persistent complement activation observed in patients with long COVID.