Frame mold serves as an important tool during autoclave process of composite panels. Its temperature uniformity plays a crucial role in guaranteeing the production quality. However, the temperature uniformity of mold usually has to be sacrificed during the design process for ensuring the stiffness of mold. To solve this problem, a novel design strategy is proposed in this study to optimize the heating airflow channels of mold with better temperature uniformity based on thermal-fluid topology optimization method. Firstly, the temperature and the airflow distribution characteristics of mold during autoclave process are investigated systematically based on the Computational Fluid Dynamic (CFD) simulation model. The result indicates that the uneven temperature distribution of the mold during autoclave process is significantly affected by the varying airflow velocity distribution inside the mold. Inspired by this, a thermal-fluid topology optimization method is developed to design the airflow channels of mold to achieve optimal mold temperature uniformity. The optimization result provides a novel configuration of mold in which a ‘wind deflector’ is incorporated inside the mold to alter the airflow pattern. Finally, the simulation results show that the optimized mold with a ‘wind deflector’ significantly improves the mold temperature uniformity by 16%. And experimental validation has applied to confirm the effectiveness of the results. Besides, the configuration of the optimized mold has good industrial application prospects for its convenient installation process and low cost.