Eugenol caprylate was synthesized using Lipozyme TLIM as the biocatalyst for the reaction. A two level Plackett–Burman (PB) experimental design was used for finding the significant reaction parameters. Response surface methodology (RSM) with a three-factor-five-level central composite rotatable design (CCRD) was further employed to study and optimize the reaction conditions. A good correlation between the predicted and actual responses showed that the generated model could adequately predict the conversion yield. The maximum conversion yield (72.2%) was obtained at the optimal condition of 65 °C, 250 rpm, 259 min, 100 mg enzyme, and 2:1 M ratio of eugenol/caprylic acid in solvent-free system.