To investigate the impact of aircraft engine nacelle aerodynamic performance on fuel economy under cruise conditions, a systematic study on nacelle aerodynamic performance optimization and its effect on block fuel consumption is performed. An aerodynamic analysis and optimization framework is established by combining iCST parameterized modeling with numerical simulations, in which Kriging surrogate modeling and the NSGA-II multi-objective optimization algorithm are employed for efficient exploration of the three-dimensional design space. A block fuel consumption model for cruise conditions is developed using the Simcenter Amesim platform, and sensitivity analysis is performed to evaluate the effects of high-speed drag, operating empty weight (OEW), and specific fuel consumption (SFC). The results indicate that block fuel consumption is highly sensitive to variations in high-speed drag and SFC. Further multi-objective optimization with drag coefficient and SFC as objectives yields a set of Pareto-optimal solutions. Compared with the baseline configuration, the optimized configuration achieves a drag reduction of approximately 0.933% under cruise conditions, corresponding to a decrease of about 0.628% in block fuel consumption. Flow field analysis shows that the optimized configuration improves transonic flow characteristics by delaying shock formation and exhibits a more gradual variation of drag over a wide range of angles of attack. The present study provides an engineering reference for the collaborative optimization of nacelle aerodynamic performance and fuel economy under cruise conditions.