Mercury (Hg) is a hazardous heavy metal that disrupts plant growth and metabolism, posing significant risks to agriculture and human health. The widespread use of Hg in industrial activities and agricultural chemicals has exacerbated Hg contamination in soil and water, resulting in severe phytotoxic effects on crops, including lettuce (Lactuca sativa L.). This study explores the potential of mannitol, an osmolyte known for its protective properties, to mitigate Hg-induced stress in lettuce. Lettuce plants were exposed to Hg stress (10 mg L−1) and treated with foliar applications of mannitol (15 mM) to assess its impact on growth, photosynthetic performance, and oxidative stress responses. Under Hg stress, lettuce exhibited a significant reduction in relative growth rate (RGR) by 31% and relative water content (RWC) by 20%. However, mannitol treatment enhanced RGR by 18% and improved RWC by 13% in Hg-stressed plants. Nutrient analysis revealed that mannitol treatment restored K, Fe, Mn, and Zn levels, which were otherwise depleted by Hg exposure. Photosynthetic parameters were adversely affected by Hg, with a 62% reduction in carbon assimilation rate (A). Mannitol treatment partially recovered A by 55% and improved PSII photochemistry, including Fv/Fm and Fv/Fo. Mannitol also moderated oxidative stress indicators, evidenced by decreased H2O2 and lipid peroxidation levels, and enhanced the activities of key antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POX), and catalase (CAT). The results indicate that mannitol treatment significantly alleviates Hg-induced phytotoxicity in lettuce by improving growth, enhancing photosynthetic efficiency, and modulating oxidative stress responses. This study highlights the potential of mannitol as a viable strategy for mitigating Hg pollution effects, offering new insights into its application for improving crop resilience under heavy metal stress.