Mezcal is a traditional Mexican spirit produced by distilling fermented agave, with a unique taste directly related to its volatile compound composition. Thus, the present research proposed the surface plasmon resonance (SPR) technique as a potential method to differentiate mezcals, studying several parameters at angular interrogations and at a fixed angle. The study evaluated eight mezcals from different agave species using SPR and gas chromatography-mass spectrometry (GC-MS). Despite the similarities in mezcal spirits corresponding to the same ethanol content and the same artisanal method, it was possible to obtain well-differentiated characteristics by SPR parameters, such as the width of the curve, the resonant angle, and reflectance intensities. Therefore, it was possible to demonstrate the potential use of the SPR technique as a rapid first approach to a screening test to differentiate types of spirits.