The emergence of drug-resistant porcine enterotoxigenic Escherichia coli (ETEC) necessitates the exploration of alternative antibacterial approaches. Two lytic bacteriophages, PES-1 and PES-2, have been isolated and characterized to control ETEC. PES-1 exhibited a wide host range, lysing five ETEC strains, whereas PES-2 displayed restricted specificity, impacting only one of the seven strains. Both phages demonstrated optimal stability at a pH of 4.0–7.0 and a temperature of 4 °C–37 °C. Comparative genomic characterization revealed that the bacteriophages PES-1 have a 40.3 kb size and 48.29% GC contents, while the PES-2 have 67.8 kb size and 46.12% GC Contents, both of which possess a double-stranded linear DNA genomes, lacking tRNA genes, lysogeny-related elements, virulence factors, and antibiotic-resistant factors, emphasizing their obligately lytic lifestyle and genomic biosafety. Genomic analysis revealed that PES-1 exhibited sensitivity to EcoR-I and Hind-III. PES-2 demonstrated resistance to all tested restriction enzymes. Combining bacteriophages with antibiotics such as amoxicillin and neomycin significantly enhanced antibacterial efficacy (p < 0.05). A notable synergy was observed with amoxicillin, resulting in a decrease in bacterial loads by 2.02–3.47 log units compared to amoxicillin alone. This synergy likely arises from dual selective pressure and improved antibiotic penetration after phage-mediated lysis. However, no significant difference was observed in the gentamycin-phage combination group compared to the phage cocktail group. The results indicate that PES-1 and PES-2 show environmental stability and effectiveness as biocontrol agents for ETEC. This research introduces an innovative method for developing bacteriophage-based solutions applicable to veterinary and food safety contexts.