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Piston diaphragm pumps are used worldwide to transport abrasive and aggressive slurries against high discharge pressures in the mining, mineral processing, and power industries. Intermittent suction and drainage of the diaphragm, however, can lead to pulsating output pressure, which has caused major problems in the application of these pumps. To improve the accuracy of simulations of piston diaphragm pumps and to enable better simulation of their pressure pulsation behavior, it is necessary to carry out a three-dimensional fluid–structure interaction simulation of the pump fluctuation characteristics. This article proposes a simplified simulation model based on the periodic motion characteristics of a piston diaphragm pump, where a ZMB240 piston diaphragm pump serves as the research object. By simplifying the numerical simulation of the model, we are able to analyze the deformation characteristics and the fluctuation characteristics of the piston diaphragm pump under different initial conditions for the pressure-stabilizing air chamber.