In recent years, composite materials with cascade nanostructure have been widely used in Surface-enhanced Raman scattering (SERS) due to their unique localized plasmonic properties and electromagnetic field synergistic enhancement effect. However, the structure-homogeneity and SERS stability still remain challenging. Herein, we proposed an efficient route of constructing large-area periodic Ag-Au composite nanostructures simply via combining confined spherization technique and in-situ substitution reaction. The results showed that the prepared Ag-Au composite nanostructure exhibited outstanding detection sensitivity and signal homogeneity for various molecules, including anticancer drug of 6-mercaptopurine (6-MP). More importantly, the prepared nanostructure showed high-stability of SERS responses after being stored for one year at room temperature. This method greatly improves the preparation efficiency of large-area uniform cascade nanostructures, and provides a reliable way to further improve the SERS activity.