Cinnamic acid is one of the phenolic compounds that is isolated from cinnamon, or other natural plants, and has a wide range of physiological activities. However, the application of cinnamic acid is limited due to its poor solubility and low oral bioavailability. In this study, the feasibility of producing octyl cinnamate by ultrasonic assistance, combined with a rotary evaporation under vacuum, was studied using methyl cinnamate and octanol as the starting materials. A Box–Behnken design (BBD) was employed to evaluate the effects of the operation parameters, including reaction temperature (55–75 °C), reaction time (4–12 h), and ultrasonic power (90–150 W) on the production of octyl cinnamate. Meanwhile, the synthesis process was further optimized by the modeling response surface methodology (RSM). The data indicated that octyl cinnamate was efficiently synthesized from methyl cinnamate and octanol using the ultrasound plus vacuum system; further, this system was superior to the conventional method. According to the RSM model for the actual experiments, a reaction temperature of 74.6 °C, a reaction time of 11.1 h, and an ultrasound power of 150 W were determined to be the best conditions for the maximum molar conversion of octyl cinnamate (93.8%). In conclusion, the highly efficient synthesis of octyl cinnamate by a rotary evaporator with an ultrasound plus vacuum system was achieved via RSM optimization.