Escherichia coli infections pose a significant threat to poultry, particularly with the rise of antibiotic resistance. This study investigates the protective and therapeutic efficacy of silver nanoparticles (Ag NPs) and zinc oxide quantum dots (ZnO QDs) in mitigating E. coli-induced hepatorenal lesions in broiler chicks. Eighty Specific Pathogen-Free broiler chicks were divided into eight groups, including negative and positive controls, and preventive and therapeutic nanoparticle protocols. On day 14, chicks were challenged with 1 × 108 CFU/ml of E. coli O78, and either Ag NPs (0.5 mg/kg) or ZnO QDs (80 mg/kg) were administered orally. Histopathological scoring, morphometric analysis of inflammatory areas, and biochemical assays were used to assess tissue damage and organ function. Histopathological examination revealed severe hepatorenal lesions in the E. coli-infected control group, including multifocal necrosis, hydropic degeneration, and inflammatory infiltration. Tubular epithelial degeneration and nephritis were prominent in the kidneys. In contrast, chicks treated with Ag NPs and ZnO QDs showed significantly reduced lesion severity, confirmed by histopathological scoring. Inflammatory areas in the liver and kidneys were markedly diminished in the treated groups compared to the infected control. Biochemical analyses confirmed these findings, showing improved liver enzymes, creatinine, and uric acid levels, indicating restoration of liver and kidney function. Ag NPs and ZnO QDs significantly decreased liver enzyme elevations and renal dysfunction observed in the infected control group, suggesting potent protective and therapeutic effects. In conclusion, Ag NPs and ZnO QDs significantly mitigated E. coli-induced hepatorenal damage, offering a promising alternative to traditional antibiotics in poultry.