An analytical protocol based on surface-enhanced Raman spectroscopy (SERS) and aimed at the detection of toxicologically relevant concentrations of JWH-018 in oral fluid is presented for the first time. A DFT-supported in-depth vibrational characterization of the drug in the solid state and in solution was also performed, providing a body of literature for future spectroscopic work on the compound. A Langmuir adsorption model was used to derive quantitative parameters such as the affinity of JWH-018 for citrate-capped gold nanospheres as well as the LOD. The application of the implemented method to the analysis of extracts from fortified oral fluid samples demonstrates the feasibility of SERS as an alternative to current immunoassays as a screening tool for use in emergency room settings.