This study investigates the wear characteristics and optimization of a centrifugal pump (Q = 25 m³/h, H = 50 m, n = 2900 r/min) applied in sediment-laden waters of Southern Xinjiang irrigation systems. A numerical framework integrating the Realizable $k-\epsilon$ turbulence model, Discrete Phase Model (DPM), and Oka erosion model was established to analyze wear patterns under varying parameters (particle size, density, and mass flow rate). Results indicate that the average erosion rate peaks at 0.92 kg/s mass flow rate. Subsequently, a Response Surface Methodology (RSM)-based optimization was implemented: (1) Plackett–Burman (PB) screening identified the inlet placement angle (A), inlet diameter (C), and outlet width (E) as dominant factors; (2) Full factorial design (FFD) revealed significant interactions (e.g., A × C, C × E); (3) Box–Behnken Design (BBD) generated quadratic regression models for head, efficiency, shaft power, and wear rate (R² > 0.94). Optimization reduced the average erosion rate by 31.35% (from 1.550 × 10⁻⁴ to 1.064 × 10⁻⁴ kg·m⁻²·s⁻¹). Experimental validation confirmed the numerical model’s accuracy in predicting wear localization (e.g., impeller outlet). This work provides a robust methodology for enhancing the wear resistance of centrifugal pumps for agricultural irrigation in water with high fine sediment concentration environments.