Acute kidney injury (AKI) is a major clinical problem associated with high morbidity and mortality, and current treatment options remain limited. Herine, phytochemical characterization, computational analyses, and the nephroprotective effects of the aqueous extract of Euphorbia echinus aerial parts were investigated, and the underlying mechanisms were explored. The phytochemical components were identified employing LC-MS/MS, and their antioxidant potential was evaluated using the DPPH radical scavenging assay, while in vivo nephroprotection was evaluated using the glycerol-induced AKI model. Rats were given 200 or 400 mg/kg of the extract, and kidney function was assessed based on serum creatinine, blood urea nitrogen, urinary albumin, urinary creatinine, and the albumin/creatinine ratio. Biomarkers of oxidative stress (GSH, catalase), inflammation (IL-1β), and apoptosis (Bcl-2) were also quantified. Molecular docking, molecular dynamics simulations, and deep learning-based affinity prediction (Boltz-2) were used to determine the interactions of the identified phytoconstituents with caspase-1. LCMS/MS analysis identified 76 phytocomponents, predominantly flavonoids, phenolic acids, and daphnane-type diterpenoids. The extract demonstrated marked antioxidant capacity, as indicated by a DPPH IC50 of 17.15 μg/mL, and its administration significantly restored renal function while attenuating oxidative stress, inflammatory cytokine production, and apoptotic signaling in a dosedependent manner. Consistent computational analyses revealed resiniferatoxin and eupatorin as strong and stable caspase-1 binders. The findings of this study demonstrate the relevance of E. echinus phytoconstituents as promising candidates for AKI management and encourage plantderived therapies against inflammasome-associated pathways.