The SARS-CoV-2 infection is spreading rapidly worldwide.Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed.Here,we discovered that protoporphyrin Ⅸ (PpⅨ) and verteporfin,two Food and Drug Administration (FDA)-approved drugs,completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 tmol/L and 0.31 tmol/L,respectively,and their EC50 values of reduction of viral RNA were at nanomolar concentrations.The selectivity indices of PpⅨ and verteporfin were 952.74 and 368.93,respectively,suggesting a broad margin of safety.Importantly,PpⅨ and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2 (ACE2).The compounds,sharing a porphyrin ring structure,were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein.Our study suggests that PpⅨ and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.