Background: Pre-clinical studies related to the use of rapamycin (Sirolimus®), a mammalian target of rapamycin (mTOR) inhibitors, for age-related macular degeneration (AMD) have shown improved therapeutic outcomes. However, knowledge of its dose–effect relationship in humans with AMD has been limited and requires further investigation. Objective: The aim of this study is to assess the safety and efficacy of Sirolimus® for treatment of AMD in humans and determine the dose range for its application in the eye. Methods: A systematic literature review was conducted following the PRISMA guidelines. The MEDLINE, Embase, CINAHL, Scopus and Cochrane Central Registry of Controlled Trials databases were searched for original clinical studies examining the effects of Sirolimus® on outcomes linked to AMD in humans. This review has been registered in the PROSPERO database. Results: Only four studies were found to satisfy the inclusion and exclusion criteria and were analyzed in this systematic review in a narrative way. The dose range of rapamycin in the limited number of studies appears to be toxic to the retina. Conclusion: Future studies should focus on establishing the optimal low-dose range of Sirolimus® that effectively induces autophagy without causing retinal toxicity, as current data indicate a potential therapeutic window that remains underexplored. Specifically, longitudinal, controlled studies with larger, heterogeneous patient populations are necessary to determine the precise dosing that balances efficacy and safety in treating AMD.