Hydroponic systems (soilless plant cultivation) offer a more sustainable solution to many environmental and resource problems, such as salinity, water scarcity, rising fertilizer and pesticide costs, environmental pollution, and soil degradation. Salinity problems affect several physiological, morphological, and biochemical processes in plants, reducing water availability, nutrient uptake, and crop yield. The agricultural sector has taken notice of nanotechnology and nanobubbles, and many important investments have been made to optimize crop yields and eliminate salinity problems. The study took place in the Greenhouse Laboratory of Perrotis College, Thessaloniki, Greece, using three hydroponic substrates (coconut fiber, hydroponic perlite, and Grodan Rockwool), in which two lettuce (Lactuca sativa L.) varieties (red oak and Romaine) were grown in 10 different sections. Moreover, the main treatments consisted of five sections utilizing a range of saline irrigation water (E.C.i: 1, 4, 8, 10, and 12 dS/m, replicated three times across substrates), enhanced with Nanobubbles through the use of two innovative electronic devices [MAXGROW (MG) + Agro-NanoBubbles (Agro-NBs)] generator. Additionally, there were another five sections of non-treated saline irrigation water (E.C.i: 1, 4, 8, 10, and 12 dS/m, replicated three times across substrates). The goal of this experiment is to examine the results of the influence of Nanobubbles with the use of two innovative electronic devices on various vegetable agronomic traits (weight and height), plant tissue analysis (macro and micro-nutrients), quality parameters (NDVI, Chlorophyll, etc.), used in high range salinity levels for two lettuce varieties. In addition, environmental conditions inside the greenhouse were recorded [CO2, Temperature (oC), humidity (%), and PAR]. The results showed that red oak and cos lettuce biomass enriched with Nanobubbles were statistically significant and increased (126 % and 38%) at high salinity (10 dS/m), compared to non-treated saline irrigation water. In conclusion, coconut fiber has shown the highest yield among the others.