BACKGROUND: Both protein disulfide isomerase (PDI) and SARS-CoV-2 main protease (M OBJECTIVES: Our goal was to identify phytochemical inhibitors of SARS-CoV-2 M METHODS: PDI, ERp57, ERp5, ERp46, isolated domains of PDI, and PDI mutants were used to evaluate the effects of galloylated polyphenols and their analogs on thiol isomerase reductase activity. Laser-injury and ferric chloride models of thrombus formation and a tail snip assay were used to assess the effects on thrombosis and hemostasis. RESULTS: Pinocembrin 7-O-(3''-galloyl-4'',6''-(S)-hexahydroxydiphenoyl)-β-D-glucose (PGHG) inhibited both PDI and SARS-CoV-2 M CONCLUSIONS: Galloylated polyphenols represent a large class of antithrombotic compounds with broad activity against thiol isomerases. Many of these compounds also inhibit SARS-CoV-2 M