Antibiotic resistance has emerged as a major challenge in oral and maxillofacial surgery (OMFS), affecting the management of odontogenic infections, postoperative complications and reconstructive procedures. The increasing prevalence of multidrug-resistant pathogens, combined with the overuse and misuse of empirical broad-spectrum antibiotics, has significantly reduced the effectiveness of conventional antimicrobial protocols. Odontogenic infections are predominantly polymicrobial, involving viridans group streptococci, Prevotella, Porphyromonas, and Fusobacterium species, whereas non-odontogenic infections increasingly demonstrate virulent nosocomial pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. Resistance mechanisms including β-lactamase production, horizontal gene transfer, ribosomal target modification, and biofilm-mediated phenotypic tolerance have further complicated treatment outcomes. 

This review discusses the evolving microbial spectrum, current resistance patterns of commonly used antimicrobials and the molecular mechanisms responsible for treatment failure in OMFS. In addition, major areas of antimicrobial misuse including prolonged perioperative prophylaxis, unnecessary prescriptions for low-risk outpatient procedures and inaccurate penicillin allergy labeling, are critically analyzed. The review also highlights evidence-based antimicrobial stewardship strategies such as single-dose perioperative prophylaxis, penicillin de-labeling protocols, culture-guided therapy, and continuous prescription audits. Appropriate integration of surgical intervention with rational antibiotic use remains essential to reduce resistance, improve clinical outcomes, and preserve the long-term efficacy of antimicrobial therapy in modern oral and maxillofacial surgery.