Globally, postpartum hemorrhage (PPH) is the top cause of maternal death. Multiple uterotonic medications are available to prevent PPH; however, it is still unclear whether one is the most effective. The current study compared the efficacy and safety of intravenous carbetocin with rectal misoprostol for the active management of the third stage of labor in order to prevent PPH. Eligible studies were found utilizing digital medical sources, including the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (WOS), PubMed, Scopus, and Google Scholar, from inception until September 2022. Only randomized controlled trials (RCTs) that matched the inclusion requirements were chosen. We used the Cochrane Risk of Bias scale (version 2) to assess the quality of the included studies. The Review Manager (version 5.4 for Windows) was used to conduct the meta-analysis. The results were summarized as mean difference (MD) or risk ratio (RR) with a 95% confidence interval (CI) in fixed- or random-effects models according to the degree of between-study heterogeneity. Collectively, we screened 621 articles after omitting duplicates and eventually included three RCTs for analysis. Overall, 404 patients were included in these studies; 202 patients were allocated to the intravenous carbetocin group whereas 202 patients were allocated to the rectal misoprostol group. Two RCTs were judged as "low" risk of bias, whereas one RCT was judged as having "some concerns" regarding the quality assessment. Regarding efficacy endpoints, the intravenous carbetocin group had significantly lower blood loss (n=3 RCTs, MD=-117.74 mL, 95% CI [-185.41, -50.07], p<0.001), need for additional uterotonics (n=2 RCTs, RR=0.06, 95% CI [0.01, 0.46], p=0.007), need for uterine massage (n=2 RCTs, RR=0.40, 95% CI [0.20, 0.80], p=0.009), and need for blood transfusion (n=2 RCTs, RR=0.38, 95% CI [0.15, 0.95], p=0.04) compared with the rectal misoprostol group. Regarding safety endpoints, the rates of diarrhea (n=3 RCTs, RR=0.18, 95% CI [0.06, 0.55], p=0.003) and chills (n=2 RCTs, RR=0.31, 95% CI [0.12, 0.83], p=0.02) were significantly lower in the intravenous carbetocin group compared with the rectal misoprostol group. However, there was no significant difference between both groups regarding the rates of headache (n=3 RCTs, RR=1.23, 95% CI [0.06, 1.91], p=0.35) and facial flushing (n=2 RCTs, RR=0.88, 95% CI [0.46, 1.68], p=0.70). In conclusion, it was discovered that intravenous carbetocin was a superior substitute for rectal misoprostol for the active management of the third stage of labor. With far fewer side effects, intravenous carbetocin decreased postpartum blood loss and further uterotonic use. For women who have a high risk of PPH, intravenous carbetocin is advised.