This study aimed to evaluate the effects of microbubbles on the growth of lettuce in hydroponic cultivation under high-salinity conditions. Lettuce (Lactuca sativa L. 'Cos lettuce') seeds were sown and then transplanted at 3 weeks after germination in a deep flow technique (DFT) hydroponic system. A 3% aqueous solution of NaCl was prepared to mimic the salinity of seawater. For microbubble treatment, 26 uniform seedlings were grown in two DFT systems, i.e., 13 seedlings in each system, and a microbubble generator was installed. A chiller and heater were installed on one side to maintain the water temperature. Microbubbles were generated throughout the experiment; the plants were grown for a total of 2 weeks, during which the pH, electrical conductivity (EC), and dissolved oxygen (DO) of the water did not change significantly compared to the control. Among the growth parameters, there were no differences in leaf length and width, but lettuce grown in the presence of microbubbles showed a significantly higher leaf number and longer root length. In addition, the shoot fresh weight and root fresh weight of the treated lettuce were 32.6% and 56% higher, respectively, than those grown in the control treatment. The dry weight of shoots and roots increased by 42% and 226%, respectively, in the microbubble treatment. These results suggest that microbubbles generated in the nutrient solution can increase the growth of salt-stressed plants in seawater-based hydroponic cultivation.