E. coli infection (colibacillosis) is among the most prevalent and significant poultry diseases due to its role in causing decreased weight gain, mortality, and reduced flock uniformity, though E. coli, as a normal flora, can be present in birds' intestinal tracts; some strains may cause respiratory and systemic diseases, referred to as avian pathogenic E. coli (APEC). The objectives of the study were to evaluate the growth performance and physiological parameters of E. coli-infected chickens treated with pomegranate extract-loaded zinc nanoparticles (PPE-ZnO-NPs). One hundred and fifty broiler chickens were allotted into five groups, consisting of 30 birds per group. In group G1, the control birds were negative; in group G2, the control-positive infected birds were positive for E. coli O87; G3, the infected birds were supplied with drinking water containing 40 mg/L of PPE-ZnO-NPs; G4, the infected-treated with 80 mg/L of PPE-ZnO-NPs given by drinking water; G5, the infected-treated with 120 mg/L of PPE-ZnO-NPs given for 35 days. The bird performance and mortalities were monitored, and blood and tissue samples were collected for biochemical, antioxidant, and pathological analysis. The mean of serum total cholesterol, triglycerides, creatinine, and urea was significantly reduced (P