Objective: To compare the efficacy of different routes of misoprostol administration (sublingual, vaginal, rectal) in reducing intraoperative blood loss, which remains a concern for the surgical management of uterine leiomyomas. Data sources: The protocol was registered in PROSPERO (CRD42025637576). Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines, we searched several databases (Ovid Medline, Embase, Scopus, Web of Science, Cochrane, Global Health, Global Index Medicus, ClinicalTrials.gov) through June 2024. Methods of study selection: The references were screened and data were abstracted in Covidence for studies meeting inclusion criteria. Title abstract screening was conducted, followed by full-text review and then data abstraction. Analyses were conducted with R. Tabulation integration and results: There were 328 studies identified in the initial search. Of those, 26 studies were included for analysis, but only 20 were able to undergo network meta-analysis against the primary outcome of interest (blood loss). Rectal misoprostol administration was associated with the largest mean reduction in intraoperative blood loss (mean difference -152.43 mL, 95% CI, -228.43 to -76.44, P<.0001), followed by vaginal administration (mean difference -69.46 mL, 95% CI, -122.11 to -16.82, P=.010). Sublingual administration was not statistically significant (mean difference -92.13 mL, 95% CI, -234.95 to 50.70, P=.206). Across other key outcomes (eg, blood transfusion, operative time), rectal misoprostol generally outperformed vaginal and sublingual modes of administration in our network meta-analysis. Conclusion: Route of misoprostol administration does matter in reducing blood loss during abdominal myomectomy with rectal administration favored, although the data are limited for sublingual administration