Grapevine adaptation to drought involves morphological, anatomical, and physiological modifications that could be viewed as a measure of drought avoidance. The main vine responses to drought consist of the regulation of carbon assimilation as a consequence of limited stomatal conductance, which is reflected in changes in plant water status. In this factorial study (2020–2021 growing seasons), two red cultivars, the local ‘Aglianico’, widely grown in Central-South Italy, and the international ‘Cabernet Sauvignon’, were used to evaluate how their interaction in three different environments can modify physiological adaptations and how yields and their qualitative traits can be modified. The lowest leaf water potential (−0.68 Mpa) for the two cultivars was registered in Molise, while the most stressed vine was found in Sicily for Aglianico (−1.86 MPa). At least in two of three locations, Molise and Campania, the detected stomatal conductance and the leaf water potential have shown that Cabernet Sauvignon can be classified as a near-isohydric cultivar, whereas Aglianico can be categorized as a near-anisohydric cultivar. The interactions between genotype x environment highlight different levels of adaptability between the two cultivars in different sites during each season. The data presented here contribute to a better understanding of the effects of genotype and environment interactions in progressive dry cultivation and how these interactions can modify the qualitative traits of grapes.