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Nigella sativa seeds have multiple industrial and pharmaceutical uses for the diseases treatment such as bronchitis, rheumatism, high blood pressure, cough, eczema, inflammation, and influenza. Although semi-arid areas are suitable for production of annual medicinal plants because they receive favorable amounts of solar radiations, the establishment of these plants’ seedling requires frequent irrigations because their seeds are small and the climate is hot at the time of planting. When the irrigation sources are limited, poor establishment and inadequate production will result. Therefore, in order to improve nitrogen (N) in N. sativa seedling establishment, different effects of seed priming treatments were evaluated under drought stress. Different levels of soil moisture (irrigation after 11, 22, 33, and 44 mm of evaporation as no water stress, mild water stress, moderate water stress, and severe water stress, respectively) and seed priming treatments [no priming, potassium nitrate (KNO3), zinc sulfate (ZnSO4), polyethylene glycol 6000, and gibberellic acid (GA)] were evaluated as the main plot and subplot factors, respectively. The results showed that under mild water stress condition, seed priming significantly increased proline content and the highest percentage of emergence was obtained with ZnSO4. Furthermore, the highest amount of soluble protein was observed in the KNO3 treatment and the catalase enzyme content increased in all priming treatments, except polyethylene glycol treatment. Under moderate water stress condition, the KNO3 treatment raised the rate and percentage of emergence and the seedling length. However, under severe water stress condition, the highest percentage of emergence was achieved by GA and ZnSO4 treatments. Moreover, hydropriming and GA produced the highest proline content and seedling dry weight. Under moderate and severe water stress conditions, the hydropriming and ZnSO4 treatments showed a significant increase in catalase activity. It can be concluded that priming of N. sativa seeds with ZnSO4 and GA can alleviate drought stress in the early stages of seedling growth by increasing the antioxidants in the seedlings. Farmers in semi-arid regions can prime N. sativa seeds with these compounds before planting to increase production of this valuable medicinal plant andreducewater consumption.