Background <p>Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, induces multisystem toxicity primarily through oxidative stress and activation of inflammatory pathways. Propolis, a natural bee-derived product rich in polyphenolic compounds, exhibits potent antioxidant and anti-inflammatory properties. This study investigated the protective efficacy of aqueous propolis against BPA-induced hepatorenal dysfunction in male rats.</p> Methods <p>Forty-two male Sprague–Dawley rats (90–120 g) were randomly allocated into seven groups (<i>n</i> = 6): control (saline), vehicle (olive oil; 5 mL/kg), BPA (10 mg/kg), propolis-low (125 mg/kg), propolis-high (250 mg/kg), BPA + propolis-low, and BPA + propolis-high. Treatments were administered orally once daily for eight weeks. Hematological parameters, hepatic enzymes (ALT, AST), renal function markers (creatinine, urea), electrolytes (Na⁺, K⁺, Ca²⁺), oxidative stress biomarkers (MDA, TAC, NO, protein carbonyl), inflammatory cytokines (IL-6, TNF-α, IFN-γ), and tissue trace elements were quantified using standardized methodologies. Liver and kidney tissues were processed for histopathological examination using hematoxylin and eosin (H&amp;E) staining, and pathological changes were graded based on the percentage of affected tissue area.</p> Results <p>BPA exposure induced significant hepatorenal toxicity, characterized by elevated transaminases, impaired renal function, and electrolyte imbalance. Profound oxidative stress and inflammatory activation were observed, accompanied by a decline in hemoglobin concentration. Histopathological examination revealed severe hepatic damage, including hepatocyte degeneration and necrosis, while renal histology showed extensive tubular epithelial necrosis, tubular dilatation with proteinaceous casts, glomerular congestion, interstitial edema, and inflammatory cell infiltration. Propolis co-administration conferred dose-dependent protection, with the high-dose regimen (250 mg/kg) restoring hemoglobin to near-normal levels, completely normalizing creatinine, reducing MDA, restoring TAC, and significantly lowering IL-6 and TNF-α levels. Histopathological analysis confirmed the protective role of propolis; high-dose treatment preserved normal hepatic architecture with minimal degenerative changes. Hepatic zinc accumulation was evident in the high-dose group, potentially contributing to the activation of antioxidant enzymes.</p> Conclusions <p>Chronic BPA exposure induces severe hepatorenal dysfunction, oxidative stress, inflammatory activation, and hematological disturbances in male rats, as evidenced by biochemical and histopathological alterations. Propolis supplementation, particularly at 250 mg/kg, demonstrated marked protective efficacy by scavenging free radicals, restoring antioxidant capacity, suppressing inflammatory mediators, and modulating trace elements. These effects were accompanied by clear histological preservation of hepatic and renal tissue architecture. Collectively, these findings highlight propolis as a promising natural protective agent against environmental endocrine disruptor-induced toxicity, warranting further translational research to explore its potential therapeutic applications in humans.</p>