In this study, a MOF-199/Ag@Au SERS sensing structure was successfully synthesized by combining metal–organic frameworks (MOFs) with surface-enhanced Raman scattering (SERS) technology for the efficient detection of dopamine (DA), a biomarker for neurological diseases, in serum. Using electrochemical methods, a copper-based MOF (MOF-199) was synthesized in situ on copper substrates and further deposited with silver nanoparticles (AgNPs). Subsequently, gold nanoshells were encapsulated around these silver cores by in situ chemical deposition. This preparation process is simple, controllable, and inexpensive. Furthermore, a novel Azo reaction-based DA SERS method was proposed to detect 1 pM DA, which represents an improvement in sensitivity by two orders of magnitude compared to previous unlabeled SERS detection methods and by four orders of magnitude compared to another SERS approach proposed in this work. There was an excellent linear relationship (R2 = 0.976) between the SERS signal at 1140 cm−1 and the DA concentration (0.001 M~1 pM). The results indicate that the MOF-199/Ag@Au sensor structure can successfully achieve both the qualitative and quantitative detection of DA in serum, thus providing a robust technical basis for the application of SERS technology in the field of clinical neurological disease screening.