During hydraulic fracturing operations of low-permeability reservoirs, packers are the key component to ensure the success of multistage fracturing. Packers enable sections of the wellbore to be sealed off and separately fractured by hydraulic pressure, one at a time, while the remainder of the wellbore is not affected. However, reliable sealing properties of the packer rubber are required to meet the high-pressure and high-temperature (HPHT) conditions of reservoirs (such as 70 MPa and 170 °C). In this study, the structures of the packer rubber with two different materials are optimized numerically by ABAQUS and validated by experiments. The optimization process starts from the packer rubber with a conventional structure, and then, the weakest spots are identified by ABAQUS and improved by slightly varying its structure. This process is iterative, and the final optimized structure of a single rubber barrel with expanding back-up rings is achieved. For the structure of three rubber barrels with metallic protective covers, both HNBR and AFLAS fail under HPHT conditions. For the final optimized structure, the packer rubber made of AFLAS can work better under HPHT than that made of HNBR which ruptures after setting. The results show that the optimized structure of a single rubber barrel with expanding back-up rings and the material AFLAS are a good combination for the packer rubber playing an excellent sealing performance in multistage fracturing in horizontal wells.