<p>Lead exposure is linked to various adverse effects on human health, including toxicity to multiple organs such as the kidneys, liver, and reproductive system. Lead induces its toxic effects through complex pathways, including mitochondrial dysfunction, oxidative stress, and inflammation. Hydrogen-rich water (HRW) has emerged as a promising therapeutic agent due to its ability to modulate redox homeostasis via regulating mitochondrial ROS production. This study aimed to evaluate the efficacy of HRW, alone and in combination with Ethylenediaminetetraacetic acid (EDTA), in alleviating the complications of acute lead poisoning in an animal model. Thirty male Wistar rats were divided into five groups: control, lead acetate (PbA), EDTA treatment, HRW treatment, and combination of HRW and EDTA. PbA was administered via intraperitoneal injection, while HRW was given through oral gavage. After one week of treatment, body weight, organ weights (liver, kidney, and testis), serum measurements, histopathological evaluations and oxidative-stress marker, malondialdehyde (MDA), and antioxidative-stress factors including superoxide dismutase (SOD) and catalase in liver, kidney, and testis were assessed. Lead acetate exposure caused systemic and organ-specific toxicity, characterized by weight loss by approximately 13% (<i>p</i> &lt; 0.001), elevated serum creatinine and liver enzymes by approximately two times, and marked histological damage in the liver, kidney, and testis. PbA increased tissue lipid peroxidation (MDA) (<i>p</i> &lt; 0.01) and decreased enzymatic antioxidant activity. HRW treatment consistently reduced MDA levels and substantially restored catalase activity in the liver and testis (<i>p</i> &lt; 0.05, <i>p</i> &lt; 0.01). EDTA alone lowered MDA in the liver by approximately 30% but failed to restore antioxidant enzyme activity in tissues. The combined HRW + EDTA treatment effectively reduced MDA levels but did not consistently restore antioxidant enzyme activities. Notably, catalase activity in the combination group was lower than that observed in the HRW-only group, indicating that the addition of EDTA did not enhance, and in some cases reduced, the catalase response compared with HRW alone. SOD activity showed no consistent or statistically significant recovery across groups. Our results showed that HRW provides statistically significant protective effects against acute lead-induced toxicity in multiple organs. Co-administration with EDTA improved some outcomes but did not consistently enhance antioxidant-enzyme activation, with HRW administration as a lone treatment outperforming the combination, and EDTA, in some the protective effects of HRW appeared to be mediated, at least in part, by restoration of catalase activity. Therefore, HRW, alone or in combination with EDTA, can be considered a promising strategy for managing lead toxicity, and further mechanistic and dosing/timing studies are warranted.</p>