Traditionally, most simulation approaches for pistons are conducted based on thermal-structure coupling, where the cooling boundary conditions are determined by empirical formulas. However, these approaches often suffer some decreases in the accuracy of the simulation results. Aiming at the problem, this paper conducts a thermal-fluid-structure coupling simulation method for the piston of a large marine diesel engine, which employs computational fluid dynamics to identify the cooling boundary conditions. Firstly, the solid and fluid models are established. Then, the cooling process of the piston chamber is simulated, with the temperature and heat transfer coefficients being mapped onto the solid component. Finally, loads and constraints are imposed on the solid component to accomplish the simulation. Under the presumed simulation conditions, the obtained coupling stresses are within the permissible range, with a maximum value of 419.68 MPa, and the dangerous region occurs at the junction of the piston head and the cooling chamber.