Freshwater resources comprise only 2.5–2.75% of all water on the Earth, 1.75–2% from them are frozen. We urgently desperately need to conserve water and find an effective alternative agriculture system. Other techniques-agricultural practices and food sources must be used to avoid disasters. We aimed to compare two farming systems (hydroponic with microbubbles or macrobubbles and sand soil) and to find the best system with the lowest cost and high production of low-water plants. We used three hydroponic system: (i) without the application of bubbles (T1), (ii) with the application of microbubbles (T2), (iii) macrobubbles (T3), and the conventional cultivation-based soil (T4). The results show significant differences in the morphological and biochemical parameters of lettuce plants grown in the hydroponic system and conventional cultivation-based soil. The morphological characteristic, chlorophyll, phenol, flavonoid content, enzymatic and non-enzymatic antioxidants, mineral content, and dissolved oxygen were significantly greater in plants grown in the microbubble hydroponic system. In addition, total soluble sugars, proline, and MDA content were significantly greater in plants grown in sand soil (T4) as compared to the plants grown in different hydroponic systems (T1, T2, T3). The results show that the water consumed in the hydroponic system is lower than used in sandy soil. Our findings suggest that the hydroponic system can increase income and reduce the amount of water consumed; therefore, plants grown in hydroponic systems with microbubbles have achieved the best plant growth, secondary metabolites, and antioxidants compared to plants grown in other systems.