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Abstract Background The prostaglandin E1 analog “misoprostol” is a drug that has powerful ecbolic effects and can be beneficial in the prevention and treatment of postpartum hemorrhage, which is the leading cause of maternal mortality worldwide. Objectives To assess the value of adding intrauterine misoprostol together with intravenous oxytocin injection compared with sublingual misoprostol together with intravenous oxytocin injection during elective cesarean section to reduce blood loss intraoperatively and prevent postpartum hemorrhage. Methods A total of 192 pregnant women were counseled and recruited from the labor and delivery unit at Kasr Al Aini Hospital, Cairo University, and equally randomized into two groups. Group (A) included 96 women who received intrauterine misoprostol (400 mg) + oxytocin. Group (B) included 96 women who received sublingual misoprostol (400 mg) + oxytocin. The primary outcome of our study was estimation of the amount of blood loss during and after cesarean delivery. The secondary outcomes were the incidence of PPH within the first 6 h after labor, the need for blood transfusion, the need for any supplementary ecbolic drugs, the need for additional surgical intervention for PPH, changes in hematocrit and hemoglobin in both groups after delivery, and the incidence of side effects of the study medications. Results We observed a significant discrepancy between the two groups in terms of postoperative Hb and Hct, postoperative differences (pre- and post-Hb and post-Hct) and EBL favoring the intrauterine group. However, no significant difference was observed between the groups with respect to excessive blood loss > 1000 ml in the 1st six hours, the need for supplementary ecbolics, the necessity for blood or blood prod, the need for additional surgical intervention (for PPH) or side effects. Conclusion Intrauterine misoprostol combined with oxytocin intravenous infusion is more effective than sublingual misoprostol combined with oxytocin intravenous infusion in lowering intraoperative blood loss and preventing postpartum hemorrhage in elective cesarean section. Trial registration This trial was retrospectively registered with the ClinicalTrials.gov Registry on 12-April-2024 (registration number: NCT06364098).