BACKGROUND: Diabetic foot ulcers (DFUs) are a severe complication of diabetes, often leading to infections caused by multidrug-resistant (MDR) bacteria, which complicate treatment and increase amputation risks. Bacteriophage (phage) therapy, targeting specific bacterial pathogens, has re-emerged as a promising alternative to antibiotics. This systematic review evaluates the efficacy of phage therapy for DFUs. METHODS: A comprehensive search was conducted in PubMed, Scopus, Web of Science, and Embase up to October 29, 2024, using keywords such as "phage therapy," "diabetic foot ulcers," and "bacteriophages." Included were original English-language studies investigating phage therapy for DFUs, while reviews and non-English articles were excluded. Data extraction and quality assessment were performed independently by two reviewers. RESULTS: Twenty-one studies demonstrated phage therapy's effectiveness against key DFU pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, and Klebsiella pneumoniae. Phage cocktails showed superior efficacy in preventing bacterial regrowth and overcoming resistance compared to single phages. Synergistic effects with antibiotics (e.g., ciprofloxacin) were observed, enhancing biofilm penetration and bacterial eradication. Case studies reported high tolerability and clinical resolution, even in antibiotic-resistant infections. However, evidence remains limited to small-scale studies. CONCLUSION: Phage therapy is a viable, safe option for MDR DFU infections, particularly due to its biofilm-disrupting properties and synergy with antibiotics. The lack of large randomized controlled trials (RCTs) underscores the need for standardized protocols, broader phage cocktails for polymicrobial infections, and optimized delivery methods. Future research should prioritize RCTs to establish efficacy, safety, and regulatory pathways for clinical adoption.