ETHNOPHARMACOLOGICAL RELEVANCE: Lead (Pb), a predominant heavy metal in the environment, causes significant harm to mammalian organs by activating oxidative stress and inflammation. Artichoke (Cynarascolymus L.) is a conventional edible botanical remedy known for its diverse pharmacological attributes, including antioxidant and anti-inflammatory properties. AIM: In this study, we aimed to investigate the effects of artichoke water extract (AWE) on Pb-induced liver toxicity and the potential underlying mechanisms. MATERIALS AND METHODS: We identified and quantified the chemical compounds in AWE using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Fifty male C57BL/6J mice (8-week-old) were randomly divided into five groups with ad libitum access to a standard diet and water. Over six weeks of experiments, the control group was orally administered 100 μL/day of distilled water. The Pb group received orally a Pb solution at 25 mg/kg body weight (BW)/day. The Pb + AWE (0.8) group received a combination of Pb solution (25 mg/kg BW) and AWE (0.8 g/kg BW) daily. Next, the Pb + AWE (1.6) group received a combination of Pb solution (25 mg/kg BW) and AWE (1.6 g/kg BW) daily. The Pb + vitamin C group received a combination of Pb solution (25 mg/kg BW) and vitamin C (50 mg/kg BW) daily. We evaluated tissue Pb levels, serum biochemical indices, liver function parameters, and histopathology post-experiment. HepG2 cells were cultured to investigate AWE's role and underlying mechanism of action on Pb-induced pyroptosis. RESULTS: Ninety-six major compounds were identified and quantified in AWE using UPLC-MS/MS. Treatment with AWE at 0.8 and 1.6 g/kg body weight (BW) significantly reduced tissue Pb accumulation, induced fecal Pb excretion, improved lipid profiles, and attenuated liver injury. In addition, AWE treatment increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity and decreased malondialdehyde (MDA), 8-OHdG production, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1 beta expression in Pb-exposed mice and HepG2 cells. Mechanistically, the in vivo and in vitro results showed that AWE's antioxidant role was related to the activation of nuclear factor-E2-related factor 2 (Nrf2) signaling. Its anti-inflammatory effect was associated with the inhibition of Pb-induced pyroptosis by inhibiting the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway. CONCLUSION: These findings indicate that AWE protects against Pb-induced liver toxicity potentially through its chelating, antioxidant, and anti-inflammatory properties.