This review was designed to examine the effect of long-term (≥2 days) vs. short-term (1 day) and single-day vs. single preoperative doses of antibiotic prophylaxis on surgical site infection (SSI) rates after orthognathic surgery. PubMed, Web of Science, Embase, and Scopus were searched for randomized controlled trials (RCTs) without any date or language restriction till 1st September 2023. SSI rates were pooled to generate risk ratio (RR). Eight RCTs comparing long-term vs. short-term and three RCTs comparing single day vs. single preoperative dose of antibiotic prophylaxis were included. Meta-analysis showed that the use of long-term antibiotic prophylaxis significantly reduced the risk of SSI after orthognathic surgery as compared to short-term antibiotics [RR:0.42 (95% CI: 0.23, 0.76) I2=0%]. Meta-analysis also noted that patients receiving a single day of antibiotic prophylaxis had significantly reduced risk of SSI as compared to those receiving only a preoperative single dose of antibiotics [RR:0.28 (95%: 0.09, 0.82) I2=0%]. Evidence from a limited number of RCTs with moderate to high risk of bias shows that two to seven days of long-term antibiotic prophylaxis reduces the risk of SSI as compared to single-day antibiotic therapy. Also, a single day of antibiotics may be more beneficial than a single pre-operative dose of antibiotic.