BackgroundWhile significant progress has been made to clarify the effects of Au and Ag nanoparticle size on SERS enhancement, research on the size effects of copper nanoparticles and copper-related nanoalloys on SERS enhancement remain scarce. Nanoscale copper (Cu) is important because of its unique sensing and catalytic properties; however, research on its size and compositional effects remains a significant challenge because of the intricate fabrication process and difficulty in preventing oxidation. ResultsOur study elucidated the size-dependent, surface-enhanced Raman scattering (SERS) of Cu NPs, particularly the sensing capabilities of both electromagnetic (EM) SERS at 1.5 × 103 and chemical enhancement (CE) SERS at 3.6 × 104 of approximately 58 nm Cu NPs. Additionally, a solution aging examination revealed preservation of the metal-related core structure, surface plasmon resonance, and SERS features of the PSMA/ONPG-coated Cu NPs for up to 7 days. With the introduction of galvanic replacement reactions and laser ablation syntheses, the incorporation of Au atoms enabled the fabrication of 7–75 nm AuxCuy nanoparticles by using the remaining Cu core after aging in water, which offered precise control over the Cu/Au ratio from 5/95 to 29/71. SERS measurements of the large AuxCuy nanoparticles amplified up to 1.4 × 104 of the EM-mediated vibrational signals from the adsorbed molecules. The strong Au–S chemical bonds of the Au-rich AuxCuy nanocrystals increased the CE SERS to 5.5 × 104, whereas the Au3Cu1 crystals at the AuxCuy interface decreased the CE SERS but improved the electron transfer for catalysis via SERS detection. SignificanceOur research provides further insight into the structural and size effects of Cu and AuCu alloys used as SERS enhancers and offers avenues for designing cutting-edge SERS catalytic sensors tailored to Cu-related catalytic reactive structures.For the first time, we also manipulated the Cu atomic structure and surface composition to understand the significance of surface effects on SERS substrates of the Cu series from a nanoscale analytical perspective.