Foliar application or minerals is a methodology to promote growth and/or yield and to protect plants against different kinds of stresses. Currently there is a great interest in evaluating the effect of nanoparticles for enhancing the effect of these treatments. This study was performed to evaluate and compare the effect of foliar application of zinc oxide (ZnO) and zinc oxide nanoparticles (ZnO-NPs) on the growth and yield of safflower under different irrigation regimes. Foliar applications of ZnO in all concentrations (4, 6, 8, 10, 12, and 14 g L−1) led to an increase in biomass yield, number of capitula per plant, number of seeds per capitulum, and grain yield of plants compared with control plants. The maximum increase in the studied traits was obtained with a ZnO concentration of 6, 8, and 10 g L−1. In a second round of experiments, we observed the effect of nanoparticles and found that spraying with ZnO and ZnO-NPs at a concentration of 10 g L−1 may ameliorate the deleterious effects of water deficit. The results of the present study support the idea that foliar application of ZnO improves safflower yield, especially under drought stress, and showed that using of nanoparticles increases the efficiency of the application.