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Hand Foot Mouth Disease (HFMD), resulting from human enterovirus A71 (HEVA71) infection can cause severe neurological complications leading to fatality in young children. Currently, there is no approved antiviral for therapeutic treatment against HEVA71 infection. In this study, a 500-compound flavonoid library was screened to identify potential inhibitors of HEVA71 using high-throughput immunofluorescence-based phenotypic screening method. Two lead flavonoid compounds, ST077124 and ST024734 at the non-cytotoxic concentration of 50 μM were found to be effective antivirals that inhibited replication of HEVA71, reducing infectious viral titers by 3.5 log10 PFU/ml and 2.5 log10 PFU/ml respectively. Our study revealed that ST077124 is a specific antiviral compound that inhibits human enteroviruses while ST024734 exhibited antiviral activity against human enteroviruses as well as dengue virus type-2. We also identified that both compounds affected the viral RNA transcription and translation machinery of HEVA71 but did not interfere with the viral internal ribosomal entry site (IRES) activity. Hence, our findings strongly suggest that ST077124 and ST024734 are effective antiviral compounds of minimal cytotoxicity and could serve as promising therapeutic agents against HEVA71 infection.A 500-compound flavonoid library was screened to identify potential inhibitor of HEVA71.ST077124 and ST024734 inhibits replication of HEVA71 at the non-cytotoxic concentration of 50 μM.ST077124 and ST024734 inhibits HEVA71 RNA transcription and translation machinery but does not interfere with IRES activity.ST077124 is a specific antiviral compound affective exclusively against enteroviruses.ST024734 exhibited antiviral activity against human enteroviruses as well as dengue virus type-2.