The steel pipe pile cofferdam method is one of the deep water foundation construction methods, which has been widely used in the foundation construction of high-speed railway bridges in China in recent years due to its economic and efficient characteristics. The deep water foundation of Xin'an River Bridge newly built in Jiande City of Zhejiang Province is constructed by steel pipe pile cofferdam. Taking the foundation bottom sealing structure as the research object, the influence of the slope foundation of the slope riverbed on the cofferdam bottom sealing structure and the stress accumulation effect in the construction process are considered. The overall model of steel pipe pile cofferdam - unequal thickness bottom sealing structure is established by MIDAS Civil finite element software. The stress deformation and anti-floating safety and stability of the bottom sealing structure of the deep water foundation in the slope foundation are analyzed. The thickness of the bottom sealing concrete is optimized and the construction measures to enhance the anti-floating stability of the bottom sealing structure of the steel pipe pile cofferdam are proposed. The numerical results show that the maximum tensile stress and deformation of the non-equal thickness bottom sealing concrete appear at the thinner part of the bottom sealing structure， and the monitoring should be strengthened during the construction process. After the thickness of the bottom sealing structure is reduced by 1 m, the maximum tensile stress and the maximum deformation of the concrete increase by 42.3 % and 56.1 % respectively,which all meet the requirements. However, the anti-floating stability of the bottom sealing structure does not meet the requirements. It is recommended to use the anti-floating anchors and other measures to increase the stability of the bottom sealing structure, which provides theoretical guidance for the design and construction of the bottom sealing structure of similar projects.