Background Cesarean section (CS) is the most frequently performed surgery in the United States. Compared to vaginal delivery, CS has a higher risk of maternal and neonatal mortality, morbidities, and complications, among which surgical site infection (SSI) is the most common. We aimed at evaluating the effectiveness of postoperative oral administration of cephalexin and metronidazole on SSI among obese women undergoing CS. Methods We conducted a randomized, double-blind clinical trial comparing the prophylactic effect of oral cephalexin and metronidazole vs cephalexin and placebo on SSI following CS among obese women. who had received preoperative prophylactic cephalosporin antibiotics. The study was conducted at the Ommolbanin Hospital, affiliated with Mashhad University of Medical Sciences from April 2019 to February 2020. Result The participants were randomized into the intervention group (n = 210) and the control group (n = 210). At week-1 follow-up, the outcomes were significantly lower in the intervention group as compared to the control group in terms of fever (9% vs 19%, p = 0.003), abnormal discharge from the incision (serous: 8.6% vs 10.5%, purulent: 2.9% vs 16.7%, p < 0.001), incision separation (1% vs 7.1%, p = 0.001), and cellulitis (4.8% vs 13.3%, p = 0.002). At week-2 follow-up, there were no patients in the intervention group with fever, abnormal discharge from the incision, incision separation, or cellulitis and there was a statistically significant difference for fever, abnormal discharge from the incision, and incision separation between the two groups (p < 0.001, p = 0.001, p = 0.014, respectively). Conclusion Post-operative administration of cephalexin and metronidazole for 48-h post-cesarean delivery among obese women, in addition to the standard pre-operative prophylaxis, reduced the overall rate of surgical site infection and wound infection symptoms in a 2-week follow-up. Trial registration The study protocol was approved by the Iranian Registry of Clinical Trials (IRCTID: IRCT20200608047685N2) on 2021-03-15.