Background: Facial angiofibromas (FAs) are common skin manifestations of tuberous sclerosis complex (TSC) that occur in up to 80% of patients. Rapamycin seems to be effective in decreasing FAs. Objective: The aim of our study was to investigate the efficacy and safety of topically applied rapamycin in TSC patients with FAs. Methods: The methods and the results were carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. PubMed/MEDLINE, SCOPUS, and Cochrane database were systematically searched until April 21, 2022, using the PICO tool (Patient, Interventions, Comparisons, Outcome). Studies regarding efficacy and/or safety of topical sirolimus for the treatment of FAs in TSC with a published full-text in English were included. Safety was assessed based on adverse effects and sirolimus’ blood levels, and efficacy was documented by clinical improvement and reduction of Facial Angiofibroma Severity Index (FASI). For Meta-analysis, Review Manager (RevMan) 5.4.1 software was used, using random-effects model and standardized mean difference (SMD) with 95% confidence interval (CI). Results: Twenty-one final studies were included. Regarding safety, in the included studies the observed adverse effects were mainly local, while the blood levels of rapamycin were within safe limits, decreasing the likelihood of systemic immunosuppression. The meta-analysis revealed a statistically significant decrease in post-treatment FASI (SMD: -1.31, 95% CI: [-1.85,-0.77], p-value <0.00001). Subgroup and sensitivity analyses indicated similar findings. No publication bias was found to this association. Conclusion: The application of topical sirolimus to FAs can safely decrease their severity in patients with TSC.