Yellow head virus (YHV) is one of the causative agents of shrimp viral disease. The prevention of YHV infection in shrimp has been developed by various methods, but it is still insufficient to protect the mass mortality in shrimp. New approaches for the antiviral drug development for viral infection have been focused on the inhibition of several potent viral enzymes, and thus the YHV protease is one of the interesting targets for developing antiviral drugs according to the pivotal roles of the enzyme in an early stage of viral propagation. In this study, a theoretical modeling of the YHV protease was constructed based on the folds of several known crystal structures of other viral proteases, and was subsequently used as a target for virtual screening-molecular docking against approximately 1364 NCI structurally diversity compounds. A complex between the protease and the hit compounds was investigated for intermolecular interactions by molecular dynamics simulations. Five best predicted compounds (NSC122819, NSC345647, NSC319990, NSC50650, and NSC5069) were tested against bacterial expressed YHV. The NSC122819 showed the best inhibitory characteristic among the candidates, while others showed more than 50 % of inhibition in the assay condition. These compounds could potentially be inhibitors for curing YHV infection.