This paper presents the impact of varying the input seismic excitation directions on the system fragility of a geometrically complex highway bridge structure. The traditional approach of fragility derivation in the principal loading directions (longitudinal and transverse) results in an under/overestimation of the system fragility. To reduce such errors, the contribution of all major vulnerable components to the system fragility in the critical loading direction must be considered. For this purpose, a series of nonlinear time-history analyses were conducted for a testbed configured geometrically curved highway bridge structure in Japan. Shear strain, ductility, and distortion strain were considered as engineering demand parameters for bearings, concrete pier, and steel piers, respectively. The demand dependency among the components was considered using the correlation coefficient matrix for fragility estimation. Subsequently, fragility functions with respect to the input loading directions were generated for the bridge components and system to quantify their sensitivity to seismic input excitation directions. The results show that the component fragility is significantly influenced by the input excitation direction. A relative comparison of the system fragility for different loading directions indicated that a 150° loading direction yielded a higher fragility demand. The findings suggest that the critical fragility assessment should not always be decided only along the principal loading directions.