A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3C) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3C in complex with determined at a resolution of 1.2 Å revealed that covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CL and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound (IC = 0.034 μM, EC = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with , compound also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.