We employed density functional B3LYP to inspect the impact of Au-decoration on a ZnO nanosheet (ZnONS) sensing performance in detection of mesalamine (MSA) drug. The interaction of the pristine ZnONS with the MSA was found to be weak, and the sensing response is about 2.8. Decorating an Au atom into the ZnONS surface increases the adsorption energy (Ead) of MSA from −5.7 to −23.7 kcal/mol. The sensing response significantly rises to 77.3 by Au-decoration. A short recovery time of 18.6 s is found for the MSA desorption from the Au-decorated ZnONS surface at 298 K. The water solvent reduces Ead of MSA to −17.8 kcal mol−1. Thus, it suggests that Au-decorated ZnONS may be highly sensitive MSA sensor with a short recovery time.