Surface-Enhanced Raman Scattering (SERS) can obtain the spectroscopic response of specific analytes. In controlled conditions, it is a powerful quantitative technique. However, often the sample and its SERS spectrum are complex. Pharmaceutical compounds in human biofluids with strong interfering signals from proteins and other biomolecules are a typical example. Among the techniques for drug dosage, SERS was reported to detect low drug concentrations, with analytical capability comparable to that of the assessed High-Performance Liquid Chromatography. Here, for the first time, we report the use of SERS for Therapeutic Drug Monitoring of the Anti-Epileptic Drug Perampanel (PER) in human saliva. We used inert substrates decorated with gold NPs deposited via Pulsed Laser Deposition as SERS sensors. We show that it is possible to detect PER in saliva via SERS after an optimized treatment of the saliva sample. Using a phase separation process, it is possible to extract all the diluted PER in saliva from the saliva phase to a chloroform phase. This allows us to detect PER in the saliva at initial concentrations of the order of 10−7 M, thus approaching those of clinical interest.