<p>The global rise of multidrug-resistant (MDR) bacteria has rendered many antibiotics ineffective, posing serious threats to public health, agriculture, and environmental safety. In response, bacteriophage therapy has re-emerged as a precise, adaptable, and sustainable antimicrobial alternative. This review presents a comprehensive analysis of phage applications across medical, veterinary, agricultural, and environmental sectors. We examine phage-bacteria interactions, including life cycles, resistance mechanisms, and phage-derived enzymes that disrupt biofilms. Clinical studies demonstrate phage efficacy in treating chronic and MDR infections, especially in vulnerable populations. This review also highlights veterinary and agricultural uses, environmental sanitation, and food safety applications under One Health frameworks. Current challenges such as narrow host range, immunogenicity, and regulatory barriers are discussed alongside innovations in synthetic biology, nanotechnology-based delivery, and phage-antibiotic synergy. We emphasize the urgent need for standardized regulations, phage banks, and large-scale clinical trials to enable global adoption. Phage therapy offers a powerful complement to antibiotics and should be integrated into future antimicrobial strategies through sustained research, policy reform, and cross-sector collaboration.</p> Graphical abstract <p></p>