Abstract: A large number of high-pier rigid frame bridges in the canyon areas are located in near-fault regions （hereinafter referred to as near-fault）， and the seismic analyses should comprehensively consider the near-fault effect， site effect， and fluid-structure interaction when they are located in the water environment such as rivers， reservoirs， etc. Currently， most near-fault seismic records are used as consistent inputs， which may underestimate the seismic response of the bridges. At the same time， the discussion on the correlation between the seismic sources， site parameters， and seismic response of the bridges is unexplored. In this paper， the stochastic finite fault method and the boundary element method are combined to generate the multi-dimensional and multi-point ground motions of the overlying water-layer canyon sites near faults， and the analysis of the seismic response of the deep-water， large-span， high-pier rigid frame bridge in the near-fault canyon site is developed. The sensitivity of the response of piers and bearings to the seismic source and site parameters is investigated from the perspective of the whole physical process between the seismic source and the structure. The results indicate that the bridge response is most sensitive to the rupture surface size. On the whole， the influence of source parameters on the bridge response is more significant than that of site parameters. The site effect leads to the difference of the mean values of curvature ductility ratios of two main piers in longitudinal and transverse directions to be 85% and 88%. There are differences in the sensitivities of the main piers and bearings to each parameter. When the dip angle of the fault is between 33°~60°， the seismic response of the bridge shows a trend of increasing first and then decreasing， and the curvature ductility ratio of the main pier can differ by 35%. The water layer has an inhibitory effect on ground motions； however， the amplification effect of hydrodynamic pressures on the seismic response of the bridge is more prominent.