This research focuses on production releasing and routing allocation problems in re-entrant mixed-flow shops. Since re-entrant mixed flow shops are complex and dynamic, many studies evaluate release plans by developing discrete event simulation models and selecting the optimal solution according to the estimation results. However, a high-accurate discrete event simulation model requires a lot of computation time. In this research, we develop an effective multi-fidelity optimization method to address product release planning problems for re-entrant mixed-flow shops. The proposed method combines the advantages of rapid evaluation of analytical models and accurate evaluation of simulation models. It conducts iterative optimization using a low-fidelity mathematical estimation model to find good solutions and searches for the optimal solution via a high-fidelity simulation estimation model. Computational results of large-scale production releasing and routing allocation problems illustrate that the proposed approach is good at addressing large-scale problems in re-entrant mixed-flow shops.