To improve the energy density of lithium-ion battery packs, lithium-ion batteries are gradually advancing towards large-size structures, which has become one of the dominant development trends in the battery industry. With large-size blade lithium-ion batteries as the research object, this paper develops a high-precision electro-thermal coupling model based on the relevant parameters obtained through basic performance experiments, explores the mechanism of battery inhomogeneity from a simulation perspective, and further proposes a design management method. First of all, the optimal intervals of capacity and temperature, as well as the characteristics of the inhomogeneity distribution for large-size cells, are determined by essential performance and inhomogeneity tests; subsequently, the electrochemical and thermal characteristics of the large-size battery are described precisely through a 3D thermoelectric coupling mechanism model, and the inhomogeneity of the temperature distribution is obtained through simulation; eventually, the optimized cell connection method and thermal management strategy are proposed based on the validated model. As indicated by the findings, the above solutions effectively ease the inhomogeneity of large-size cells and significantly boost the performance of large-size cells under different operating conditions.