The stability of steel plate composite girder bridge is an important factor that must be considered in design. In this paper, the finite element method is used to analyze the overall stability and local stability of long-span steel plate composite girder bridge under single factor by selecting the cross beam spacing, height-span ratio, web height-thickness ratio and flange width-thickness ratio as the key design parameters. The orthogonal experimental method was used to analyze the multi factor combination of the bridge, and the importance of each design parameter was evaluated from the aspects of structural safety and economy. The results show that the safety factor of stability of steel plate girder bridge is positively correlated with the height-span ratio, and negatively correlated with the cross beam spacing, web height-thickness ratio and the flange width-thickness ratio. As far as the whole bridge is concerned, the cross beam spacing has the greatest influence on safety factor of stability and its value should be less than 15 m; the web height-to-thickness ratio has the greatest influence on the amount of steel, and its value should be between 100 and 120. The results of this paper will make this type of bridge structure more reliable and less costly.