This investigation was conducted outdoors in two separate pot experiments at College of Agriculture, Isfahan University of Technology, Iran. Each experiment was arranged as factorial based on a randomized complete block design with three replications. In the first experiment, the responses of thirteen safflower genotypes were evaluated to foliar application of bulk and nano-sized zinc oxide. In the second experiment, the effects of bulk and nano-sized zinc oxide on four safflower genotypes (Eritra, Afghanestani, Mesri and Autrishi that showed considerable and different responses to the application of Zn in the first experiment), were studied under irrigation levels based on 50 and 75 percent depletion of available soil water. In the first experiment, chlorophyll content, leaf area, shoot dry weight, numbers of buttons per plant, numbers of grains per plant, 1000 grain weight and grain yield in most evaluated genotypes were significantly increased and the extent of increases was different among genotypes. The interaction between zinc oxide foliar application and genotype was significant for shoot dry weight. The increase in shoot dry weight due to zinc oxide application varied from 3 to 48 percent. The application of nano-sized as compared to bulk form of zinc oxide increased shoot dry weight in some genotypes but decreased it in some other genotypes. In the second experiment, chlorophyll and caretonoid content, leaf area, shoot dry weight, plant height, Zn concentration and shoot dry weight were decreased but chlorophyll a/b ratio and the activities of antioxidant enzymes were increased under irrigation based on 75 compared to irrigation based on 75 percent depletion of available soil water. The decrease in shoot dry weight due to water deficit ranged from 16 to 38 percent among different genotypes. The foliar application of zinc oxide caused significant increases in chlorophyll content, caretonoid content and the activities of antioxidant enzymes CAT, APEX and POX in the second experiment. The positive effects of nano-sized compared to bulk form of zinc oxide were greater on these attributes. The application of nano-sized as compared to bulk form of zinc oxide increased shoot dry weight in Afghanestani (18%) and Eritra (22%) genotypes but decreased it in Mesri (25%) and Autrishi (12%) genotypes. The results from this study showed that there were significant differences among safflower genotypes in response to water deficit and that the effect of nano-sized of zinc oxide safflower plants was genotype dependent. Key words : safflower, genotypes, irrigation level, foliar application, zinc oxide, nano-particles, antioxidant enzymes.