<p>There is a narrow gap between Zn essentiality and toxicity in crop plants, making Zn amendment to be a puzzling question, particularly under calcareous soil and saline water conditions. We aimed to study the response of safflower to Zn supply in a calcareous soil deficient in available Zn and a less-calcareous soil with sufficient available Zn and saline water, using two pot experiments. In Experiment-I, six safflower genotypes exposed to four levels of Zn amendment (no Zn application, foliar applied Zn, soil applied Zn, and soil + foliar applied Zn) in a calcareous Zn-deficient soil. In Experiment-II, three selected genotypes exposed to the mentioned levels of Zn in the Zn-sufficient soil under different salinities (0 and 120 mM NaCl in irrigation water). Data of Experiment-I suggested some genotypic differences and, in the meantime, commonality of improvement in chlorophylls and carotenoids concentrations, leaf area, leaf Zn concentration, plant height, achenes/plant, 100-achenes weight, capitula/plant, achene weight/plant, and plant above-ground dry mass (SDM) in response to Zn amendment. Results of Experiment-II were, in contrast, indicative of commonality of suppressions in the chlorophylls and carotenoids, maximum efficiency of photosystem II, leaf area, relative water content, K, plant height, achenes/plant, 100-achenes weight, capitula/plant, achene weight/plant, and SDM, despite increases in Na/K, proline, Na, malondialdehyde, H₂O₂, and grain Zn concentrations, and antioxidative enzymes activities particularly upon exposure to soil + foliar applied Zn. The above-mentioned findings are novel, as they depict Zn application as a double-edged sword, favoring growth, physiology, and grain yield in Zn-deficient calcareous soil but contrastingly, exerting phytotoxic effects on safflower under Zn-sufficient less-calcareous soil and saline irrigation water.</p>