COVID‐19 has been proposed to be an endothelial disease, as endothelial damage and oxidative stress contribute to its systemic inflammatory and thrombotic events. Polyphenols, natural antioxidant compounds appear as promising agents to prevent and treat COVID‐19. Polyphenols bind and inhibit the F1Fo‐ATP synthase rotary catalysis. An early target of polyphenols may be the ectopic F1Fo‐ATP synthase expressed on the endothelial plasma membrane. Among the pleiotropic beneficial action of polyphenols in COVID‐19, modulation of the ecto‐F1Fo‐ATP synthase, lowering the oxidative stress produced by the electron transfer chain coupled to it, would not be negligible.