Potential degradation products (DPs), even in small concentrations, can cause changes in pharmacological and toxicological properties of a drug with a significant impact on product quality and safety. Thus, their stability and understanding of possible degradation mechanisms have a significant importance. Although liquid chromatography is the conventional technique used for forced degradation studies with excellent accuracy and reproducibility, the main disadvantages of the technique are being expensive and time-consuming. As a powerful technique, surface-enhanced Raman scattering (SERS) can be an alternative with its high sensitivity, easy sample preparation and low cost. In this study, the degradation of both tofacitinib (TOF), a Janus kinase inhibitor, and methotrexate (MTX), an inhibitor of tetrahydrofolate dehydrogenase, are studied using SERS under hydrolytic, oxidative and thermal conditions using mesoporous silica coated silver nanoparticles (Si@AgNPs) as SERS substrates. The study demonstrated that the degradation of the tested drugs using Si@AgNPs as SERS substrates could be monitored through the spectral changes on SERS spectra of drugs under several degradation conditions.