Established evidence suggests that in ARDS, platelets may exhibit a dysregulated state that exacerbates lung injury. We review evidence that suggests this platelet-mediated lung injury, while present in ARDS in general, is amplified in COVID-19 ARDS in particular. Driven by a quantifiably higher degree of platelet activation and ensuing platelet serotonin liberation into plasma compared to ARDS of other etiologies, the plasma serotonin excess in COVID-19 may be responsible for many of the devastating pulmonary and extra-pulmonary clinical manifestations of the severe disease. There is ample evidence and biologic plausibility to suggest that effective serotonin receptor (5HT-2) antagonism may reverse serotonin-mediated pulmonary vasoconstriction, lessen pulmonary platelet trapping, inhibit platelet activation and aggregation, normalize increased respiratory drive, mitigate risk of pulmonary fibrosis, and counteract adverse renal, neurologic, and cardiovascular phenomena in severe COVID-19. Given we have a well-tolerated, safe, and inexpensive oral 5HT-2 antagonist, cyproheptadine, we hope to build consensus for the need to urgently investigate 5HT-2 receptor antagonism as a treatment option for severe COVID-19.