Disease inflicted by avian pathogenic Escherichia coli (APEC) causes economic losses and burden to the poultry industry worldwide. In this study, the efficacy of chitosan nanoparticles loaded ΦKAZ14 (C-ΦKAZ14 NPs) as an oral biological therapy for Colibacillosis was evaluated. C-ΦKAZ14 NPs containing 107 PFU/ml of ΦKAZ14 (Myoviridae; T4-like coliphage) bacteriophage were used to treat experimentally APEC-infected COBB 500 broiler chicks. C-ΦKAZ14 NPs and ΦKAZ14 bacteriophage were administered orally in a single dose. The clinical symptoms, mortality, and pathology in the infected birds were recorded and compared with those of control birds that did not receive C-ΦKAZ14 NPs or naked ΦKAZ14 bacteriophage. The results showed that C-ΦKAZ14 NP intervention decreased mortality from 58.33 to 16.7% with an increase in the protection rate from 42.00 to 83.33%. The bacterial colonization of the intestines of infected birds was significantly higher in the untreated control than in the C-ΦKAZ14 NP-treated group (2.30×109 ± 0.02 and 0.79×103 ± 0.10 CFU/mL, respectively) (P ≤ 0.05). Similarly, a significant difference in the fecal shedding of Escherichia coli was observed on d 7 post challenge between the untreated control and the C-ΦKAZ14 NP-treated group (2.35×109 ± 0.05 and 1.58×103 ± 0.06 CFU/mL, respectively) (P ≤ 0.05). Similar trends were observed from d 14 until d 21 when the experiment was terminated. Treatment with C-ΦKAZ14 NPs improved the body weights of the infected chicks. A difference in body weight on d 7 post challenge was observed between the untreated control and the C-ΦKAZ14 NP-treated group (140 ± 20 g and 160 ± 20 g, respectively). The increase was significant (P ≤ 0.05) on d 21 between the 2 groups (240 ± 30 g and 600 ± 80 g, respectively). Consequently, the clinical signs and symptoms were ameliorated upon treatment with C-ΦKAZ14 NPs compared with infected untreated birds. In all, based on the results, it can be concluded that the encapsulation of bacteriophage could enhance bacteriophage therapy and is a valuable approach for controlling APEC infections in poultry.