The spatial cross-correlated diffusion of colloidal particles is often used as an essential tool to study the dynamic properties of a fluid because it directly describes the hydrodynamic interaction between two particles in a fluid. However, the experimental measurement of cross-correlated diffusion can be substantially modified by even a weak shear flow. In this work, the effect of a shear flow on spatial cross-correlated diffusion is demonstrated using experimental measurements that show a clear dependence on pair angles. An analytical solution is proposed to explain the experimental observations. A numerical simulation is performed to systemically demonstrate the influence of shear flow on spatial cross-correlated diffusion. The results of the experiment, theoretical analysis, and numerical simulation agree well with each other. Therefore, this research provides a sensitive experimental method to determine the weak shear flow in any quasi-two-dimensional fluid systems.