There has been a long fundamental pursuit to enhance and levitate the Raman scattering signal intensity of molecule by a huge number of ~ 14–15 orders of magnitude, to the level comparable with the molecule fluorescence intensity and truly entering the regime of single-molecule Raman spectroscopy. In this work we report unambiguous observation of single-molecule Raman spectroscopy via synergic action of electromagnetic and chemical enhancement for rhodamine B (RhB) molecule absorbed within the plasmonic nanogap formed by gold nanoparticle sitting on the two-dimensional (2D) monolayer WS2 and 2 nm SiO2 coated gold thin film. Raman spectroscopy down to an extremely dilute value of 10–18 mol/L can still be clearly visible, and the statistical enhancement factor could reach 16 orders of magnitude compared with the reference detection sample of silicon plate. The electromagnetic enhancement comes from local surface plasmon resonance induced at the nanogap, which could reach ~ 10–11 orders of magnitude, while the chemical enhancement comes from monolayer WS2 2D material, which could reach 4–5 orders of magnitudes. This synergic route of Raman enhancement devices could open up a new frontier of single molecule science, allowing detection, identification, and monitor of single molecules and their spatial–temporal evolution under various internal and external stimuli.