An innovative heat-integrated column configured with a side-reactor was developed for ethylbenzene (EB) production. To achieve an economical design, the total annual cost, as an objective function, was minimized by optimizing the reactor volume, the number of side reactors, the number of column trays, the reactor side-return tray, and the column pressure. The proposed side-reactor column (SRC) configuration reduces capital, energy, and total annual costs by 13.6, 12.9, and 13.2%, respectively, compared to a conventional process for the same desired yield and purity. In addition, the multiple effect heat integration was examined on the proposed configuration for energy efficiency. The resulting heat-integrated side reactor (HI-SRC) configuration further reduces capital, energy, and total annual costs by 14.8, 53.0, and 38.3%, respectively.