Parametric optimization is an important step for any mechanical system design, including the development and design of a hybrid electric bus. To obtain an optimized parameter grouping of the EQ6110HEV hybrid electric bus for best fuel economy, an orthogonal experiment design method is applied to the parameter optimization process of the EQ6110HEV hybrid prolusion system. This paper proposes two orthogonal experiment methods; the basically orthogonal experiment method and the synthetically orthogonal experiment method. By this means, the development time and the testing costs are reduced, and the impact of factors and their optimal levels are obtained by a range analysis of the experiment results. The results show that the fuel economy of the optimized parameter grouping is improved by 4.1 percent for the four-stage urban driving cycle in China and by 8.7 percent for the Wuhan urban driving cycle of public buses in China, in comparison with that of the parameter grouping of the current configuration.