OBJECTIVES: This systematic review aimed to analyze the existing literature to determine the most effective and safe duration of antimicrobial treatment in odontogenic infections of the mandible, addressing a critical gap in clinical guidelines regarding optimal treatment duration. MATERIALS AND METHODS: A systematic review protocol was registered in PROSPERO (CRD42024551258), and a comprehensive search was conducted in databases including PubMed, Web of Science, Scopus, ScienceDirect, Embase, and Google Scholar for articles published up to June 16, 2024. Randomized clinical trials (RCTs) evaluating different durations of antimicrobial treatment were prioritized. RESULTS: The database search yielded 3,446 articles. After removing duplicates using Rayyan© software, 2,653 articles remained, of which 26 met the inclusion criteria. Following a thorough evaluation, 8 studies were deemed highly relevant and included in the final analysis. The findings suggest that shorter antibiotic regimens, typically ranging from 3 to 5 days, are effective when combined with surgical interventions, minimizing complications and bacterial resistance. CONCLUSIONS: The evidence indicates that the choice of antibiotic regimen and its duration should be tailored to the patient's clinical condition, the severity of the infection, and local bacterial resistance patterns. While amoxicillin and its derivatives are effective for most cases, alternative antibiotics such as ciprofloxacin or metronidazole may be more suitable in specific scenarios. These findings highlight the importance of individualized treatment plans and the need for further randomized clinical trials to refine evidence-based guidelines.