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Kratom, Mitragyna speciosa, is one of the most popular herbs in the West and Southeast Asia. A number of previous works have focused on bioactive alkaloids in this plant; however, non-alkaloids have never been investigated for their biological activities. Antiviral and virucidal assays of a methanol leaf extract of Kratom, M. speciosa, revealed that a crude extract displayed virucidal activity against the SARS-CoV-2. Activity-guided isolation of a methanol leaf extract of Kratom led to the identification of B-type procyanidin condensed tannins of (-)-epicatechin as virucidal compounds against SARS-CoV-2. The fraction containing condensed tannins exhibited virucidal activity with an EC 50 value of 8.38 μg/mL and a selectivity index (SI) value >23.86. LC-MS/MS analysis and MALDI-TOF MS identified the structure of the virucidal compounds in Kratom as B-type procyanidin condensed tannins, while gel permeation chromatograph (GPC) revealed weight average molecular weight of 238,946 Da for high molecular-weight condensed tannins. In addition to alkaloids, (-)-epicatechin was found as a major component in the leaves of M. speciosa, but it did not have virucidal activity. Macromolecules of (-)-epicatechin, i.e., procyanidin condensed tannins, showed potent virucidal activity against SARS-CoV-2, suggesting that the high molecular weights of these polyphenols are important for virucidal activity., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)