Existing single-zone or two-zone synergistic optimization technologies have limited performance improvements for the large natural draft wet cooling towers (LNDWCTs). To further improve the cooling performance of the LNDWCTs, this study proposes for the first time a three-zone (water-spraying, fillings and rain zones) synergistic optimization method from a global optimization perspective. The 3D numerical calculation model is created and validated. Then, this work investigates emphatically the impact of the different three-zone parameters on the cooling performance, including the partition water distribution radius (R1 = 20 ∼ 60 m), the water distribution percentage in the inner zone (γ=5 ∼ 90 %), the fillings partition radius (R2 = 0 ∼ 65 m), the total coverage area of the split-flow plate (S = 2000 ∼ 2900 m2), the installation angle (θ=0 ∼ 27°), the split-flow plate length (L = 15 ∼ 55 m) and number (n = 3 ∼ 10). The simulation results illustrate that, within the studied range, the water temperature drop, cooling efficiency and Merkel number increase and then decrease with the increasing R1,γ, R2, θ and n, and increase successively with the increasing S and L. The optimized three-zone parameter combination scheme is R1 = 55 m, γ=75 %, R2 = 50 m, S = 2900 m2, θ=6°, L = 55 m and n = 7. Compared to the LNDWCT without any optimization technology, the water temperature drop, cooling efficiency, Merkel number, ventilation and evaporation loss of the cooling tower with optimized three-zone synergistic pattern increase by 0.58 °C, 3.37 %, 0.17, 1480 kg/s and 41.28 kg/s, respectively. This study can lay a theoretical basis for the multi-zone synergistic optimization research of LNDWCTs and provide a reference for the technical modifications and engineering applications.