Cadmium (Cd) toxicity represents a major constraint on plant growth and food safety by disrupting photosynthesis, redox homeostasis, and ion transport. This study investigated the modulatory role of nitric oxide (NO), supplied via sodium nitroprusside (SNP), in alleviating Cd-induced stress in three lettuce varieties (Lactuca sativa L.): curly (var. crispa), romaine (var. longifolia), and iceberg (var. capitate). Plants were exposed to 200 and 500 µM Cd with or without SNP application under controlled greenhouse conditions. Cd exposure significantly decreased biomass production, photosynthetic pigment contents, and the accumulation of essential mineral nutrients, including potassium (K⁺), calcium (Ca²⁺), iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn), while significantly enhancing oxidative stress indicators such as hydrogen peroxide (H₂O₂), melondyaldehyde (MDA), membrane permeability (MP), and proline content. Antioxidant enzyme activities responded differentially to Cd exposure: catalase (CAT) activity was stimulated, whereas ascorbate peroxidase (APX) activity was suppressed, indicating a pronounced redox imbalance. Exogenous SNP application effectively restored CAT and APX activity, stabilized cellular membranes, and attenuated oxidative damage. Cd accumulation indices—translocation factor (TF), total accumulation rate (TAR), net accumulation (NetAcc), and bio-concentration factor (BCF)—revealed substantial Cd uptake and translocation, particularly in curly and iceberg lettuce. Notably, SNP significantly reduced these indices, suggesting NO-mediated restriction of Cd mobility through enhanced root sequestration and vacuolar detoxification mechanisms. Moreover, SNP improved the homeostasis of K⁺, Ca²⁺, Fe²⁺, and Mn²⁺, highlighting its role in maintaining selective ion transport and redox balance under Cd stress. Among the varieties, curly lettuce exhibited the highest NO-induced tolerance, followed by iceberg and romaine lettuce, demonstrating genotype-dependent regulation of antioxidant defense and detoxification pathways. Overall, the findings identify NO as a multifaceted regulator that integrates redox control, ionic stability, and Cd detoxification to enhance physiological resilience and reduce Cd accumulation in lettuce.