The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure−activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC₅₀ = 0.56 μM; antiviral EC₅₀ = 9.1 μM) and the corresponding (R)-Me 15g (IC₅₀ = 0.32 μM; antiviral EC₅₀ = 9.1 μM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein−ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.