Under the global water crisis, utilizing low-quality water sources in agriculture for irrigation has offered an effective solution to address the shortage of water. Using an excess of low-quality water sources may cause serious risks to the environment, which threaten crop safety and human health. Three kinds of irrigation water (0.413, 1.44, and 2.84 dS m−1) were selected under foliar-applied bio-nanofertilizers of selenium (100 mg L−1) and copper (100 mg L−1) in individual and/or combined application. The nanofertilizers were tested on the production of tomato under greenhouse. After harvesting, the quality of tomato yield and soil biology was evaluated. Using saline water for irrigation caused many main features in this study such as increasing the accumulation of salts, soil organic matter, and CaCO3 in soil by 84.6, 32.3, and 18.4%, respectively, compared to control. The highest tomato yield (2.07 kg plant−1) and soluble solids content (9.24%) were recorded after irrigation with low water quality (2.84 dS m−1) and nano-Cu fertilization. The plant enzymatic antioxidants and soil biological activity were decreased in general due to the salinity stress of irrigation water. After 30 days from transplanting, all studied soil biological parameters (soil microbial counts and enzymes) were higher than the same parameters at harvesting (80 days) under different categories of water quality. The values of all soil biological parameters were decreased by increasing water salinity. This study was carried out to answer the question of whether the combined nanofertilizers of selenium and copper can promote tomato production under saline water irrigation. Further investigations are still needed concerning different applied doses of these nanofertilizers.