For preparation of surface-enhanced Raman scattering (SERS) substrate with high stability, reproducibility, and sensitivity performances, graphene/Ag nanoparticles were chosen to make further improvement by introducing molecularly imprinted polymer (MIP) film to protect Ag nanoparticles. The thickness of the resulting ultra-thin MIP layer is 2 nm on the surface of Ag nanoparticles. The preparation of two-dimensional/core-shell structure SERS substrate (G/Ag@MIP) possesses high SERS activity toward the probe of bovine serum albumin (BSA) target molecule, which exhibits a 10(-12) M detection limit. The G/Ag@MIP shows good selectivity and recycle rate in the detecting process. These results show that the hybrid material as a SERS sensor is potential for medical diagnosis in life sciences.