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Diabetic foot ulcers (DFUs) are a serious diabetes-related complication characterized by high rates of amputation and mortality. Emerging evidence suggests that DFUs are not simply the result of infection, but also involve microbiome dysbiosis, which impairs healing. Systemically, disturbances to the gut microbiota via the gut-skin axis promote systemic inflammation and metabolic dysfunction. Locally, skin microbial diversity is significantly reduced, allowing opportunistic pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa to form resilient biofilms. These biofilms resist antibiotics and host immunity, while microbial virulence factors exacerbate tissue damage and disrupt the healing cascade. This synergy between host pathology and dysbiosis perpetuates chronic ulceration. Novel therapeutic strategies therefore aim to modulate this aberrant ecology by shifting from broad-spectrum eradication to targeted restoration. Promising approaches include probiotics, phage therapy, traditional Chinese medicine, and faecal microbiota transplantation, which seek to recalibrate the microbiome and promote healing. However, translation into clinical practice requires more robust evidence from large-scale trials. Future perspectives point towards personalized microbial medicine, integrating multi-omics data and artificial intelligence to match interventions with specific microbial ecotypes, which may reduce the global burden of DFUs.