Preparation conditions of Fe–Cu–Ag trimetallic particles were optimized by single-factor and response surface methodology (RSM) batch experiments to obtain high-reactive Fe0-based materials for p-nitrophenol (PNP) removal. Under the optimal conditions (i.e., Fe0 dosage of 34.86 g L−1, theoretical Cu mass loading of 81.87 mg Cu/g Fe, theoretical Ag mass loading of 1.15 mg Ag/g Fe, and preparation temperature of 52.1 °C), the actual rate constant (kobs) of PNP reduction in 5 min was 1.64 min−1, which shows a good agreement between the model prediction (1.85 min−1) of RSM and the experimental data. Furthermore, the high reactivity of Fe0-based trimetals was mainly attributed to the plating order of transition metals (i.e., Ag and Cu). Furthermore, we propose a new theory that the pyramid trimetallic structure of Fe–Cu–Ag could improve the electron transport and create active sites with high electron density at the surface (Ag layer) that could enhance the generation of surface-bonded atomic hydrogen ([H]abs) or the direct reduction of pollutant. Moreover, Fe–Cu–Ag trimetallic particles were characterized by SEM, EDS, and XPS, which also could confirm the proposed theory. In addition, the leached Cu2+(<10 μg L−1) and Ag+ (below detection limits) in Fe–Cu–Ag system could be neglected completely, which suggests that Fe–Cu–Ag is reliable, safe, and environment friendly. Therefore, Fe–Cu–Ag trimetallic system would be promising for the removal of pollutants from industrial wastewater.