The emergence of multidrug-resistant (MDR) bacteria has significantly compromised the effectiveness of conventional antibiotics, necessitating the exploration of alternative therapeutic strategies. Bacteriophages, or phages, have garnered renewed interest as potential agents against MDR infections, particularly those caused by ESKAPE pathogens, which include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. This review discusses the unique mechanisms by which bacteriophages target and kill these pathogens, highlighting their potential advantages over traditional antibiotics. The article also explores recent advancements in phage therapy, including isolation techniques, in vitro and in vivo efficacy studies, and innovative engineering approaches to enhance phage activity. Despite the promise of phage therapy, challenges such as host immune responses, regulatory hurdles, and production standardization remain. Future research directions are outlined to improve phage therapy's efficacy and integration with existing antimicrobial strategies. Overall, bacteriophage therapy represents a promising avenue for mitigating antimicrobial resistance and improving clinical outcomes in the treatment of infections caused by ESKAPE pathogens.