Climate change can alter precipitation patterns, disrupting the natural water cycle and generating drought periods that negatively impact crop yield or plant survival. Novel biotechnological approaches are being developed to face water deficits. Specifically, molecular knowledge of the plant hormone abscisic acid (ABA) can be harnessed to develop genetic and chemical approaches to cope with abiotic stress. ABA receptor agonists are promising molecules that activate ABA signaling on demand and show long-lasting effects, in contrast to the exogenous application of ABA, which has a short half-life. In this work, we studied the effect of the iSB09 agonist on tomato plants grown under drought stress or well-watered conditions. iSB09 treatment induced stomatal closure in tomato through activation of PYL1-like and PYL4-like ABA receptors. Additionally, RNA-seq analyses reveal coordinated upregulation by ABA or iSB09 of the genes encoding enzymes involved in the synthesis of the osmoprotective galactinol and raffinose family of oligosaccharides. Foliar spraying of iSB09 under drought conditions anticipated the regulation of transpiration, promoted drought avoidance and increased water use efficiency in tomato plants. Physiological analysis of agonist-treated plants reveals increased CO2 assimilation and effective quantum yield of the photosystem II under drought conditions in iSB09-treated plants compared to mock-treated. Faster regulation of transpiration at the start of the drought period was achieved by iSB09 treatment, and, as a result, water consumption was reduced compared to mock-treated plants. Overall, the agonist treatment mounts the genome-wide transcriptional response to stress and increases water use efficiency under drought conditions and plant protection.