Importance: Antibiotic prophylaxis is widely used after surgical procedures operating on the mucosal tissues of the aerodigestive tract, but the optimal duration of these prophylactic therapies is often unclear. Objective: To compare short-course antibiotic prophylaxis (≤24 hours) vs extended-course antibiotic prophylaxis (≥72 hours) after ear, nose, throat, and oral and maxillofacial surgery. Data Sources and Study Selection: Literature searches of PubMed were completed in October 2017 and included prospective trials that compared antibiotic prophylaxis courses of 24 hours or less vs 72 hours or more after ear, nose, throat, and oral and maxillofacial surgery. Some studies were also handpicked from reference lists of studies found with the initial search terms. All analysis was performed between September 2017 and October 2018. Data Extraction and Synthesis: All review stages were conducted in consensus by 2 reviewers. Data extraction and study quality assessment were performed with the Cochrane data extraction form and the Cochrane risk of bias tool. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for reporting. The fixed-effects Mantel-Haenszel method was used for meta-analysis. Main Outcomes and Measures: Relative risk (RR) of surgical site infections, microbial origins of surgical site infections, adverse events, duration of hospital stay, and treatment costs. Results: Included in the meta-analysis were 21 articles with a cumulative 1974 patients. In patients receiving 24 hours or shorter vs 72 hours or longer antibiotic prophylaxis regimens, no significant difference was found in the occurrence of postoperative infections in the pooled population (RR, 0.90; 95% CI, 0.67-1.19), or in the ear, nose, throat (RR, 0.89; 95% CI, 0.54-1.45), and oral and maxillofacial populations (RR, 0.88; 95% CI, 0.63-1.21), separately. No heterogeneity was observed overall or in the subgroups. Patients receiving extended-course antibiotic prophylaxis were significantly more likely to develop adverse events unrelated to the surgical site (RR, 2.40; 95% CI, 1.20-3.54). Conclusions and Relevance: No difference was found in the occurrence of postoperative infections between short-course and extended-course antibiotic prophylaxis after ear, nose, throat, and oral and maxillofacial surgery. Therefore, a short course of antibiotic prophylaxis is recommended unless documented conditions are present that would be best treated with an extended course. Using short-course antibiotics could avoid additional adverse events, antibiotic resistance development, and higher hospital costs. Future research should focus on identifying risk groups that might benefit from prolonged prophylaxis.