Abstract: Plants use hydrogen sulfide (H2S) and nitric oxide (NO) to communicate various developmental and stress-related signals. This research aimed to examine how H2S and NO affect the tolerance of Solanum lycopersicum L. to the toxicity of cadmium (Cd) and lead (Pb). Both Cd and Pb supplementation had detrimental effects on tomato seedlings, leading to reduced seed germination, root-to-shoot ratio, fresh and dry weight, chlorophyll content, and relative water content (RWC). Furthermore, these heavy metals caused increased electrolyte leakage, malondialdehyde (MDA) accumulation, proline levels, and changes in the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX). However, when H2S and NO were applied externally, they mitigated the harmful effects induced by Cd and Pb. Their exogenous treatment led to enhanced seed germination, root-to-shoot ratio, fresh and dry weight, as well as improvements in chlorophyll content and RWC. Moreover, they reduced electrolyte leakage, MDA accumulation, proline levels, metals uptake and modulate the activity of antioxidant enzymes. Gene expression analysis revealed that, exposure of Cd/Pb, upregulated the genes responsible for antioxidant enzymes (SlSOD, SlCAT, and SlAPX), while the genes involved in H2S and NO biosynthesis (SlLCD1, SlLCD2, and SlNR) were also found modulated. The study provides physiological and biochemical evidence for H2S/NO mediated-alleviation of heavy metal stress in tomato, and can be applicable in other crops. © Pleiades Publishing, Ltd. 2024.