With the aim of enhancing both reliability and fatigue life of gasket, this study combines finite element analysis, orthogonal experimental design, dynamically-guided multi-objective optimization, and the non-dominated sorting genetic algorithm with elitist strategy to optimize the geometric parameters of the cylinder gasket. The finite element method was used to analyze the temperature field, thermal-mechanical coupling stress field, and deformation of cylinder gasket. The calculation results were experimentally validated by measured temperature data, and comparison results show that the maximum error between calculated value and experiment value is 7.1%, which is acceptable in engineering problems. Based on above results and orthogonal experiment design method, the effects of five factors, including diameter of combustion chamber circle, diameter of coolant flow hole, length of the insulation zone between third and fourth cylinders, thickness of gasket, and bolt preload, on three indexes: temperature, stress, and deformation of gasket, were examined in depth. Through the variance analysis of the results, three important factors were identified to proceed later calculation. The dynamically guided multi-objective optimization strategy and the non-dominated sorting genetic algorithm were effectively used and combined to determine the optimal geometric parameters of cylinder gasket. Furthermore, calculation results suggest that temperature, stress, and deformation of the optimized cylinder gasket have been improved by 27.88 K, 16.84 MPa, and 0.0542 mm, respectively when compared with the origin object, which shows the excellent performance of gasket optimization and effectiveness of the proposed optimization strategy.