The scarcity of high-quality water for irrigation in semi-arid zones often leads to the use of alternative sources, such as sewage effluents, brackish groundwater and reject brine from desalination plants by reverse osmosis of low-quality water and high salinity. The salts in reject brine can impair crop development and growth but can also contribute to crop nutrition. The aim of this study was to establish the ideal nitrogen, phosphorus, and potassium fertilization for soursop seedlings under irrigation of reject brine and supply water to achieve the best growth, ion homeostasis, and physiological parameters. The randomized block design was used in a 2 x 5 factorial scheme with four replications under greenhouse conditions. Two types of irrigation water (supply water with an electrical conductivity of 0.5 dS m(-1) and reject brine with 3.5 dS m(-1)) and five different NPK doses were used: 25, 50, 75, 100, and 125% of the recommended fertilizer dose of 100:300:150 mg dm(-3) of N:P2O5:K2O. For soursop seedlings irrigated with low-salinity water, the appropriate NPK fertilization was 95:285:143 mg dm(-3) of N:P2O5:K2O. Under reject brine irrigation, the soursop seedlings showed better results with 54:162:81 mg dm(-3) of N:P2O5:K2O. Adequate fertilization for soursop irrigated with reject brine improved seedlings' growth, ion homeostasis, and photosynthetic efficiency. The appropriate dose of NPK fertilization not only enables the use of reject brine and fertilizer savings for producing soursop seedlings but also avoids the negative effects of salt stress. This approach is both economically beneficial and environmentally sustainable.