A heat pump is applied in pressure-swing distillation (PSD) for separating an isobutanol/isobutyl acetate mixture in this paper. To ensure dry compression and prevent compressor damage, a preheater is added before the compressor based on the dry fluid property of the isobutanol/isobutyl acetate mixture. In addition, the optimal preheated temperature of the overhead vapor stream may further improve the performance of the heat pump-assisted PSD process. Through optimization and analysis, the optimum superheat values of overhead vapor streams from two columns are 12 and 8.4 degrees C, respectively. The coefficients of performance of heat pumps achieve maximum values of 17.18 and 20, and the total annual cost of the process is minimum. Moreover, a heat exchanger network (HEN) is applied in the heat pump with preheater-assisted PSD (HPPSD) to reduce the use of steam in preheaters. Compared with the conventional PSD, the total annual costs, energy consumption, and CO2 emission of the HPPSD-HEN process are decreased by 69.8, 83.99, and 79.58%, respectively.