Caffeic acid (CA) is a medicinal component with high medical value. It is widely applied in antibacterial and antiviral applications. In particular, caffeic acid and its derivatives have a enormous function in antitumor. Nowadays, there are many researches about caffeic acid. However, most of them are about the medicinal properties of caffeic acid, as a result the investigation of the microstructure of caffeic acid molecules is necessary. So far, there are no theoretical and experimental studies about the surface-enhanced Raman scattering spectroscopy (SERS) of CA on Ag surface. It is worth noting that the research on the vibrational spectrum and surface enhancement mechanism of caffeic acid can be a variety of pharmaceutical mechanisms of caffeic acid. Therefore, a combine surface-enhanced Raman scattering (SERS) and density functional theory (DFT) techniques are applied to conduct a comprehensive study of the adsorption properties and surface enhancement mechanism of caffeic acid on Ag nanoparticles, which can provide a scientific explanation to the medicinal properties of caffeic acid. This has important reference for advancing their related research in medicine and other fields. In this paper, surface-enhanced Raman spectroscopy of CA molecules on the surface of Ag nanoparticles was studied using combined SERS and DFT techniques. Ag nanoparticles were prepared using trisodium citrate and silver nitrate under heating and stirring using the principle of thermal reduction reaction and conventional Raman scattering (NRS) spectra and SERS spectra of CA molecules were measured usingthe laser confocal micro-Raman spectrometer. In terms of theoretical calculations, we applied B3LYP method to optimize the molecular configuration of caffeic acid, the adsorption configuration of Ag4, the adsorption configuration of carboxyl group and Ag4, and the configuration of adsorption of Ag4 by both hydroxyl and carboxyl groups, using 6-31+G** and LANL2DZ as the basis set for C, H, O, and Ag, respectively. Then, the NRS spectra of CA molecules and the SERS spectra of three possible adsorption models were calculated and compared with experimental results. At the same time, the vibration mode of CA molecules was confirmed. According to the experimental data and theoretical results, the peak at 452 cm-1 was attributed to the coupling of the torsional bending vibration and the —OH out-of-plane bending vibration, which indicated that the phenolic hydroxyl group on the CA molecule have a weak interaction with the Ag nanoparticle. We speculated that the CA molecular plane may not be perpendicular to the surface of the Ag substrate. The peak appearing at 1 338 cm-1 was attributed to COO— stretching vibration, which indicated that the carboxyl group on the CA molecular is vertically adsorbed with the Ag nanoparticle. The results showed that CA molecules adsorbed on the surface of Ag nanoparticles with carboxyl groups and phenolic hydroxyl groups as adsorption sites. At the same time, we have identified the vibrational modes of CA molecules in detail. This work has an important effect on the further applications of caffeic acid in biomedicine and other fields.