Purpose: To evaluate whether Siamese crocodile plasma exhibits antibacterial properties and if it synergizes with ceftazidime against ceftazidime-resistant Enterobacter cloacae (CREnC). Methods: Protein fractions were from crocodile plasma and tested them on CREnC strains. Multiplex polymerase chain reaction (PCR) screening test was performed for extended-spectrum β-lactamase (ESBL) phenotype and AmpC gene. The effects of the antibacterial agents were analyzed using a bacterial suspension standard curve, minimum inhibitory concentration (MIC), Checkerboard assays, viability curves, membrane permeability assays, enzyme assays, and transmission electron microscopy. Results: CREnC strains expressed ESBL-AmpC gene combinations. The MICs of resuspended protein 1 (P1), protein 5 (P5), ceftazidime, cefotaxime, and benzylpenicillin against all tested CREnC and E. coli strains were in the range of > 1024 µg/mL, indicating resistance. However, P1 and P5 exhibited a synergistic effect against test CREnC and E. coli strains when used in combination with ceftazidime and cefotaxime, with fraction inhibitory concentration indices of < 0.062 and 0.28, respectively. A kill curve demonstrated that the combination treatments had synergistic activity and inhibited β-lactamase. Conclusion: The synergistic activity of P1 and P5 in combination with ceftazidime is achieved in multiple ways, including increased cytoplasmic and outer membrane permeability, β-lactamase inhibition, and peptidoglycan damage. Therefore, the combination therapy of Siamese crocodile plasma and ceftazidime may be a novel therapeutic approach for treating recalcitrant E. cloacae infection.