Background: The use of antibiotics in diabetic foot ulcer infections (DFUI) is essential in reducing morbidity. Optimal administration of antibiotics can improve clinical outcomes and reduce the risk of antibiotic resistance. This study aims to review the efficacy, in terms of clinical cure, of various regimens and the duration of antibiotic administration in DFUI patients, based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The efficacy based on microbiological response is also reviewed as the secondary outcome. Materials and Methods: We used three databases, namely PubMed, Scopus, and ScienceDirect, to search for randomized controlled trials (RCTs) in patients with DFUI who required antibiotics. Results: A total of 16 studies were included in the systematic review. The study locations and bacterial patterns varied, with the most common pathogen being Staphylococcus aureus. Most studies did not demonstrate a significant difference in clinical cure and pathogen eradication, either in the comparison between systemic and topical antibiotics or in the duration of administration. Some studies had similar characteristics and were analyzed to conclude. These studies showed that ertapenem had comparable efficacy to piperacillin/tazobactam. Similar results were also conducted from studies of piperacillin-+amoxicillinclavulanic acid vs. moxifloxacin. Conclusion Most studies have heterogeneous characteristics, possibly due to differences in research location. Therefore, there is no strong evidence to recommend a specific antibiotic with the highest efficacy. However, since all included studies are RCTs, this review provides a good summary in considering antibiotic choices when treating DFUI patients.