Lead is one of the cursed substances that threaten all human life. Lead poisoning can occur through food or water contaminations and it is hard to be detected. This incognito metal accumulates over time and resides in the liver, kidneys, and brain tissues leading to serious medical conditions, affecting organ functions, causing failure, kidney tubule degeneration, and destroying neuronal development. However, known metal chelators have bad negative effects. Asparagus officinalis (AO) is a promising herb; its root extract exhibited antioxidant, antiapoptotic, protective, and immunomodulatory activities. Inspired by those reasons, this study investigated to which extent Asparagus extract affected male mice’s renal toxicity caused by lead acetate (LA) and antioxidant defense system. This work screened for its nephroprotective activity in four mouse groups: negative and positive control, LA group with renal injury, and diseased but pretreated mice with AO extract (AOE). Kidney index and kidney function biomarkers were evaluated. Antioxidant activities, lipid peroxidation, superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), nitric oxide (NO), and reduced glutathione (GSH) were also tested. Furthermore, inflammatory cytokine (tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)), inducible nitric oxide synthase (iNOS), renal pro-apoptotic protein (Bax), antiapoptotic protein (Bcl-2), and caspase-3 levels were evaluated. The results showed that LA administration induced oxidative stress, renal inflammation, apoptosis, and renal histopathological alteration. However, due to its antioxidant activities, AOE was found to restrain oxidative stress, therefore preventing inflammation and apoptosis. Collectively, AOE perfectly clogged lead poisoning sneaking, stopped the bad deterioration, and succeeded to protect kidney tissues from toxicity, inflammation, and apoptosis.