Acetaminophen and N-acetyl cysteine (NAC) are being used as supportive care in patients suffering from coronavirus disease 2019 (COVID-19). The coagulopathy and cerebral hemorrhage have been recently reported in these patients . Prolonged acetaminophen use increases the international normalized ratio (INR) and the risk of bleeding among patients taking anti-coagulants . Inhibition of vitamin K epoxide reductase (VKOR) by acetaminophen and NAC in chronic applications has been reported, however, detailed knowledge of the molecular mechanism and binding sites are not clear . Herein, we built the homology model of human VKOR (hVKOR) using ITASSER server, confirmed, and applied it for docking analysis of its interaction with acetaminophen and its metabolite, N-acetyl-p-benzoquinone imine (NAPQI), and NAC . We also calculated the lipophilicity and predicted the blood-brain-barrier (BBB) permeation of NAPQI by Swiss ADME . Our analysis showed that NAPQI and NAC, but not acetaminophen, bind strongly to the similar sites in hVKOR via both hydrogen and van der Waals bonding; particularly with Cys135 . Thus, it interrupted the vitamin K reducing electron transfer pathway . Further, molecular dynamic (MD) simulation study revealed that the interactions of the ligands with hVKOR are stable . In conclusion, our analysis shed a light on the molecular mechanism of acetaminophen-induced coagulopathy previously reported in some clinical cases with chronic acetaminophen use . Furthermore, considering the anti-coagulopathy of NAPQI and NAC but not acetaminophen, the BBB permeation potency of these agents, and the risk of coagulopathy in COVID-19, we suggest a regular prothrombin time (PT) and INR monitoring of these patients taking acetaminophen and/or NAC.Communicated by Ramaswamy H. Sarma.