In order to enhance the exhaust waste heat recovery efficiency of the automotive exhaust-based thermoelectric generator (TEG) system, a three-segment heat exchanger with folded-shaped internal structure for the TEG system is investigated in this study. As the major effect factors of the performance for the TEG system, surface temperature, and thermal uniformity of the heat exchanger are analyzed in this research, pressure drop along the heat exchanger is also considered. Based on computational fluid dynamics simulations and temperature distribution, the pressure drop along the heat exchanger is obtained. By considering variable length and thickness of folded plates in each segment of the heat exchanger, response surface methodology and optimization by a multi-objective genetic algorithm is applied for surface temperature, thermal uniformity, and pressure drop for the folded-shaped heat exchanger. An optimum design based on the optimization is proposed to improve the overall performance of the TEG system. The performance of the optimized heat exchanger in different engine conditions is discussed.