<p><?tk 4?>Mezcal is a traditional Mexican alcoholic spirit distilled from the fermented must of cooked agave plants. Its volatile composition depends on the agave species, region of origin, and production method. This study aimed to explore the relationship between sensory descriptors and physico-chemical properties of Oaxacan mezcals produced from <i>Agave potatorum</i>, <i>A. angustifolia</i>, and <i>A. karwinskii</i>, using either ancestral or artisanal techniques. Volatile organic compounds (VOCs) were analyzed using GC–MS, while methanol, higher alcohols, and furfural were quantified by gas chromatography coupled to flame ionization detection (GC-FID). Sensory profiling was conducted using Napping and quantitative descriptive analysis (QDA). Napping effectively differentiated mezcals by region. QDA identified <i>A. potatorum</i> mezcal from the Valles Centrales Region (VC-R) as the most floral, and <i>A. karwinskii</i> mezcals from the VC-R, Central District (C-D), and Sierra Sur Region (SS-R) as the least bitter. The clay aroma was associated with ancestral mezcals from the SS-R. Type 2 partial least squares regression (PLS-2) revealed that the floral notes in <i>A. potatorum</i> mezcal correlated with ethyl esters; the burning sensation in <i>A. angustifolia</i> mezcal with 1-butanol and 2-butanol; and the smoky descriptor in <i>A. karwinskii</i> mezcal with dibutyl phthalate.</p> Graphical abstract <p></p>