Drought stress poses a significant threat to global food security, impacting grapevine growth and development through physiological, biochemical, and molecular alterations. Cerium oxide nanoparticles (CeO₂ NPs) have recently gained attention as a potential solution to environmental challenges, yet their application in grapevines remains understudied. This study examined the interaction between foliar-applied CeO₂ NPs (at concentrations of 0, 5, 50, and 500 mg L⁻¹) and drought stress (at 30% and 70% of field capacity humidity) in grapevine saplings. Among the different concentrations tested, 50 mg L⁻¹ CeO₂ NPs significantly improved the agronomic traits (e.g., shoot length, leaf area, shoot and root dry weights), photosynthetic parameters (stomatal conductance, chlorophyll a and chlorophyll b) and RWC of the grapevine saplings under drought stress. In parallel, CeO₂ NPs significantly induced the activity of compatible solutes and SOD, CAT and APX under drought stress conditions. Moreover, the availability of CeO₂ NPs alleviated drought stress-induced damage in grapevine saplings, as evidenced by decreased H₂O₂ (32.63%), EL (40.35%) and MDA (50.63%) levels. The molecular results revealed that CeO₂ NPs caused significant changes in gene expression under drought stress by reducing the expression of the VvCLH1, VvCu/ZnSOD, VvRD29A and VvRBOHA genes by 4.54-fold, 27.73-fold, 14.6-fold and 46.12-fold, respectively. These findings suggest that CeO₂ NPs applied via leaves enhance grapevine sapling resistance to drought-induced oxidative stress through cooperative enzymatic and nonenzymatic antioxidant mechanisms, influencing gene regulation. As a result, these findings revealed that CeO₂ NPs could be promising elicitor candidates for alleviating drought stress in grapevines.