Background: When it occurs after a cesarean section or a normal vaginal delivery, postpartum hemorrhage (PPH) is a potentially fatal obstetric emergency. Aims and objectives: The aim of the study was to compare the efficacy and safety of oxytocin against oxytocin plus misoprostol in avoiding PPH during active management of the third stage of labor (AMTSL). Materials and Methods: Using simple randomization, 150 women from the labor ward of the Department of Obstetrics and Gynaecology at the Indore Medical College were recruited and randomly allocated to either test Group A or test Group B. Standard pharmacological treatment, including intramuscular injection of 10 IU of oxytocin and other components of AMTSL criteria, was administered to patients in Group A. In addition to the other components of the AMTSL criteria, Group B patients got the usual pharmacological treatment of 10 IU of oxytocin through the injectable route and 600 g of misoprostol through the oral route. Various characteristics of both groups were compared, including parity, gravida, delivery style, PPH etiology, blood transfusion, and surgical intervention. Results: Mode of delivery was vaginally seen in 85% and 92% and cesarean in 15% and 8%. Etiology was uterine atony in 54% and 64%, retained tissue in 26% and 12%, laceration in 11% and 18%, and coagulopathy in 9% and 6%. Blood transfusion was needed in 27% and 57% and surgical intervention in 82% and 68% in Groups A and B, respectively. A statistically significant difference was observed (P ≤ 0.05). Conclusion: The results of this study support the use of misoprostol in hospital settings as an adjunct to oxytocin since it reduces the incidence of PPH, eliminates the need for intrusive interventions, and ultimately reduces maternal mortality.