Tyrosinase is a metalloprotein that contains copper ions in its active site. Because of the existence metal ions in the binding site, it is difficult to model the interactions of tyrosinase with its inhibitors with conventional molecular mechanical calculations. (S)-(+)-decursin and its derivatives have been shown to exhibit activities with tyrosinase. In order to elucidate the binding mode of (S)-(+)-decursin and its derivatives with mouse tyrosinase (mTyr) and human tyrosinase (hTyr), for which co-crystals have not been solved, we adopted homology modeling, quantum mechanics/molecular mechanics (QM/MM) method, docking, and molecular dynamics to predict the structure of the complexes. Our results show that (S)-(+)-decursin and all of its derivatives have an ester group that forms a hydrogen bond with key residue in the binding site of tyrosinase. In addition, the compounds interact with histidine and hydrophobic residues of the structure. Our research would be helpful in studying the structure of the tyrosinase active site for a purpose of developing tyrosinase inhibitors.