Raman, surface-enhanced Raman scattering, and shell isolated nanoparticles-enhanced Raman scattering techniques were used to study the indigo-nanoparticle interaction nature. Silver nanoparticles were employed with and without a silicon dioxide spacer inert layer. The SERS spectral profile, obtained using silver nanoparticles, is different from the Raman one, which led to the proposition that the indigo-silver interaction is in the range of intermolecular interactions. SERS spectral reproducibility suggests identical organization and orientation of the analyte on the metal surface. The shell isolated nanoparticles enhanced Raman scattering spectrum of indigo, obtained by using silicon dioxide coated silver nanoparticles resulted similar to its Raman spectrum. This result indicates that the indigo structure is chemically unmodified by the silicon dioxide-coated silver surface. From the shell-isolated nanoparticles-enhanced Raman scattering experiments, the electromagnetic mechanism is proposed as the reason for the spectral enhancement. Theoretical calculations allow one to infer both the indigo-silver surface interaction nature and the orientation of indigo on the surface.