The use of desalinated seawater (DSW) as an alternative to conventional water resources is gradually gaining more interest due to the strong water deficit and increasing pressure on water resources in semi-arid regions. Furthermore, the combination of this alternative irrigation with the hydroponic cultivation system would allow continuous production almost through the whole year and hydroponic-related high crop yield. Nevertheless, the effects of DSW irrigation in hydroponic systems on the product quality need to be firstly studied to avoid product quality losses. In this study, we evaluated the effects on the quality of two tomato cvs. (Ramyle and Racymo) of three different irrigation treatments (T1, DSW; T2, DSW/well water mix; and T3, well water) under hydroponic or traditional cultivation systems. The soluble solid content of samples (highly correlated to dry matter content) grown under hydroponic conditions and T3 irrigation showed the highest values (5.8 °Brix) although such differences (<0.6 °Brix) with T1 might not be sensorially appreciated. Similarly, although T3 samples showed higher acidity than T1 samples, such differences (0.06%) would be not appreciated by the consumer. Tomatoes grown in hydroponic conditions had 1.1–1.2-fold higher firmness than conventional soil conditions showing hydroponic T3 samples had the highest value (21–23 N). Tomato cv. Racymo displayed higher color index (chroma) than cv. Ramyle, registering hydroponic T1 samples the most intense red color correlated with the highest lycopene content of 41.1 mg/kg. T1 irrigation of tomatoes cv. Ramyle did not induce significant changes while differences lower than 10% were observed in the tomato cv. Racymo. The highest total antioxidant capacity, which was highly correlated to the total phenolic content (R2 = 0.80), was found for hydroponic T1 samples with 1637/1243 µmol/kg for the tomato cvs. Ramyle/Racymo. Conclusively, the use of DSW would not compromise the consumer acceptance of tomatoes due to the low (not appreciable) quality differences, with even the total antioxidant capacity of these samples being increased. Furthermore, the mix of DSW with conventional water resources (lower cost) would not compromise the tomato quality.