Background: Phage therapy, a treatment utilizing bacteriophages to combat bacterial infections, is gaining attention as a promising alternative to antibiotics, particularly for managing antibiotic-resistant bacteria. This study aims to provide a comprehensive review of phage therapy by examining its safety, efficacy, influencing factors, future prospects, and regulatory considerations. The study also seeks to identify strategies for optimizing its application and to propose a systematic framework for its clinical implementation. Methods: A comprehensive analysis of preclinical studies, clinical trials, and regulatory frameworks was undertaken to evaluate the therapeutic potential of phage therapy. This included an in-depth assessment of key factors influencing clinical outcomes, such as infection site, phage–host specificity, bacterial burden, and immune response. Additionally, innovative strategies—such as combination therapies, bioengineered phages, and phage cocktails—were explored to enhance efficacy. Critical considerations related to dosing, including inoculum size, multiplicity of infection, therapeutic windows, and personalized medicine approaches, were also examined to optimize treatment outcomes. Results: Phage therapy has demonstrated a favorable safety profile in both preclinical and clinical settings, with minimal adverse effects. Its ability to specifically target harmful bacteria while preserving beneficial microbiota underpins its efficacy in treating a range of infections. However, variable outcomes in some studies highlight the importance of addressing critical factors that influence therapeutic success. Innovative approaches, including combination therapies, bioengineered phages, expanded access to diverse phage banks, phage cocktails, and personalized medicine, hold significant promise for improving efficacy. Optimizing dosing strategies remains a key area for enhancement, with critical considerations including inoculum size, multiplicity of infection, phage kinetics, resistance potential, therapeutic windows, dosing frequency, and patient-specific factors. To support the clinical application of phage therapy, a streamlined four-step guideline has been developed, providing a systematic framework for effective treatment planning and implementation. Conclusion: Phage therapy offers a highly adaptable, targeted, and cost-effective approach to addressing antibiotic-resistant infections. While several critical factors must be thoroughly evaluated to optimize treatment efficacy, there remains significant potential for improvement through innovative strategies and refined methodologies. Although phage therapy has yet to achieve widespread approval in the U.S. and Europe, its accessibility through Expanded Access programs and FDA authorizations for food pathogen control underscores its promise. Established practices in countries such as Poland and Georgia further demonstrate its clinical feasibility. To enable broader adoption, regulatory harmonization and advancements in production, delivery, and quality control will be essential. Notably, the affordability and scalability of phage therapy position it as an especially valuable solution for developing regions grappling with escalating rates of antibiotic resistance.
