Oral and maxillofacial space infections (OMSIs) are potentially life-threatening polymicrobial conditions requiring timely and appropriate antimicrobial therapy. We conducted a systematic review and meta-analysis of 53 studies (12,408 cases) to evaluate microbial epidemiology and resistance patterns. Streptococcus was the predominant pathogen (45.51%), followed by Prevotella (15.89%) and Porphyromonas (15.61%). Methicillin-resistant Staphylococcus aureus (MRSA) accounted for 19.18% of S. aureus isolates. Diabetic patients exhibited a higher prevalence of Klebsiella (27.09% vs. 8.13% in nondiabetics). Antimicrobial resistance was lowest for levofloxacin (11.03%) and cephalosporins (16.83%), and highest for gentamicin (39.66%) and erythromycin (39.35%). The microbiological landscape and antimicrobial resistance patterns were influenced by multiple factors, including infection source, diabetic status, diagnostic methods, national income level, and temporal trends. Incorporating these variables with local antimicrobial surveillance data can support more targeted and effective empirical therapy. Well-designed, representative studies across diverse settings are urgently needed to optimize antimicrobial use amid rising resistance.
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