Picornaviruses are non-enveloped viruses that represent a large family of positive-sense single-stranded RNA viruses including a number of causative agents of many human and animal diseases such as coxsackievirus B3 (CVB3) and rhinoviruses (HRV). In this study, we performed a high-throughput screening of a compound library composed of approximately 6000 small molecules in search of potential picornavirus 3C protease (3C(pro)) inhibitors. As results, we identified quinone analogues that effectively inhibited both CVB3 3C(pro) and HRV 3C(pro) with IC50 values in low micromolar range. Together with predicted binding modes of these compounds to the active site of the viral protease, it is implied that structural features of these non-peptidic inhibitors may act as useful scaffold for further anti-picornavirus drug design and development.