Surgical site infections (SSIs) represent one of the most important complications occurring postoperatively following surgical procedures. The SSI incidence is higher following gastrointestinal (GI) surgeries compared to any other surgery. It contributes to the majority of morbidity and mortality in patients undergoing GI surgeries. The accepted practice worldwide for the prevention and control of SSIs is providing antimicrobial prophylaxis. The appropriate antimicrobial and dose are chosen depending on the microbial flora, complications, and patient risk factors. The objective of this review was to determine the sufficient number of prophylactic antimicrobial doses that would be efficacious and safe in controlling the SSIs following GI ontological surgeries. Single-dose antimicrobial prophylaxis has shown the same efficacy as the multipl-dose antimicrobial regimen in controlling SSIs in esophageal, gastric, and colorectal surgeries. The advantages of a single-dose regimen include less chance of emergence of resistance, less chance for allergies or toxicity, and less cost. The addition of metronidazole with single-dose antimicrobial prophylaxis in colorectal surgery should be considered due to its beneficial effect in further reducing infections. Further randomized controlled trials are needed for the literature to determine the efficacy and safety of single-dose antimicrobial prophylaxis in patients undergoing esophageal and colorectal surgeries. In addition, studies are required to determine the individual effectiveness of metronidazole in controlling SSIs in colorectal surgeries.