Cu 2 O nanospheres (NSs) were synthesized by modifying the glucose reduction method. Based on this method, Cu 2 O/Au (Ag) NSs were further prepared by in situ reduction of HAuCl 4 (via electron beam evaporation of Ag). With Rhodamine 6G (R6G) as probe, the surface-enhanced Raman scattering (SERS) characteristics of the three samples were systematically studied. The experiment results showed that the enhancement factor (EF) of Cu 2 O/Au (Ag) NSs as 1.25 × 10 8 (2.74 × 10 9 ) and the ultralow detection limit (LOD) as 8.07 × 10 –12 (1.13 × 10 –13 ) M for R6G. The excellent performance of SERS may be due to the charge transfer (CT) between metal–semiconductor (MS) molecules and the strong electromagnetic field (E-field) of each hot spot. In addition, discrete dipole approximation (DDA) simulations were performed to simulate the E-field enhancement of the Cu 2 O and Cu 2 O/Au (Ag) NSs in a three-dimensional (3D) configuration. These further supported that the high SERS performance for R6G is because of the powerful E-field coupling between neighboring Au (Ag) NPs and the surface plasmon resonance (SPR) effect. The Cu 2 O/Ag NSs have potential in applications such as biomedicine, food safety, and environmental monitoring because of their high sensitivity and good reproducibility.