Background: The active management of the third stage of labor is crucial for preventing postpartum hemorrhage (PPH), a leading cause of maternal mortality. Syntocinon (oxytocin) and Misoprostol are prominent pharmacological agents used to manage this stage by inducing uterine contractions and minimizing blood loss. Objective: This study aimed to compare the efficacy of 10 IU intravenous Syntocinon and 800 µg sublingual Misoprostol in the active management of the third stage of labor, focusing on maternal outcomes, blood loss, side effects, and the need for additional interventions. Methods: A randomized controlled trial was conducted in the Department of Obstetrics and Gynaecology at Hayatabad Medical Complex from August 1, 2021, to February 1, 2022. A total of 284 women aged 18-40 years with singleton pregnancies were enrolled and randomized into two groups of 142 each. Group A received 800 µg of sublingual Misoprostol, while Group B received 10 IU intravenous Syntocinon at the delivery of the anterior shoulder of the baby. The third stage of labor was managed with early cord clamping and controlled cord traction. Blood loss was meticulously recorded, and patients were monitored for 24 hours postpartum. Data were analyzed using IBM SPSS Statistics version 25, with continuous variables expressed as mean ± standard deviation and categorical variables as frequencies and percentages. Post-stratification analysis utilized an independent sample t-test, with a p-value of ≤ 0.05 considered statistically significant. Results: The mean age of participants was 29.507±3.24 years in the Misoprostol group and 28.352±3.77 years in the Syntocinon group. Blood loss was slightly lower in the Misoprostol group (242.4 ± 3.72 ml) compared to the Syntocinon group (249.176 ± 4.07 ml). The majority of participants were aged 18-30 years (69.7% in Group A and 71.1% in Group B). No statistically significant differences were observed in blood loss based on age, gestational age, or parity. Conclusion: Misoprostol offers practical advantages in terms of ease of administration and stability at room temperature, making it a viable alternative, especially in low-resource settings. Both Misoprostol and Syntocinon are effective in managing the third stage of labor, with comparable efficacy in reducing blood loss.