Antibiotic resistance in pathogens like E. coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa poses a major threat to global health, with limited treatment options. This study systematically evaluated the efficacy of bacteriophage therapy in vitro and in vivo against multidrug-resistant strains. Phage treatment led to significant bacterial reduction (up to 4.5 log₁₀ CFU/mL) and improved survival rates in mice (up to 85%). Synergistic effects with antibiotics and preservation of gut microbiota were observed without adverse reactions. These findings highlight phage therapy as a promising, targeted, and safe alternative for managing resistant infections.