Soil salinization is a severe environmental issue limiting the growth and yield of crops worldwide. Subsurface drip irrigation with micro-nano bubble hydrogen water (SDH) is an innovative way to realize the role of hydrogen gas (H2) in improving plant resistance to salt stress in practical agricultural productions. Nonetheless, limited information is available on how SDH affects the plant salt tolerance performance. Especially, the underlying physiological respond, hormone-regulated and soil microbial-mediated mechanisms have not been reported so far. In this study, the effects of SDH on lettuce (Lactuca sativa L.) growth, photosynthesis, root development, antioxidant system, phytohormone, and soil microbial community were investigated under normal and salt stress conditions. The results showed that, with salt stress, SDH significantly enhanced the lettuce fresh weight, photosynthesis activity, and root growth. The leaf antioxidant enzyme activities increased and reactive oxygen species (ROS) content decreased to reduce the oxidative damage. The decreased malondialdehyde (MDA) content indicated a low membrane lipid peroxidation responsible for cellular damage. SDH also helped to maintain osmotic homeostasis, which was reflected by the increased soluble protein (SP) content. Reduced Na+/K+ ratio and ROS did not trigger excessive production of stress response hormones abscisic acid (ABA) and jasmonic acid (JA), which alleviated the mediated growth inhibition effects. SDH enriched the abundance of the plant growth-promoting rhizobacteria (PGPR) in the soil, such as Arthrobacter and Pseudomonas. That might be the reason for explaining the increase in hormone indoleacetic acid (IAA) in lettuce and 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity in the soil, which was beneficial for inhibiting ethylene production and promoting plant growth. Under the normal condition, variations of physiological and growth indicators as affected by SDH were similar to those under the salt stress condition, except for root development. High concentration of dissolved hydrogen gas in water might expel the oxygen. The induced soil anoxic environment limited oxygen diffusion, in turn inhibited root respiration and growth. The effect of hydrogen concentration on the plant tolerance against salt stress under different salt content could be further studied.