Introduction: Over the years, paclitaxel-coated balloons (PCBs) have been considered a standard treatment for femoropopliteal (FP) lesions due to their higher efficacy compared to noncoated balloon angioplasty. However, some studies have raised concerns about a potential link between PCBs and increased long-term mortality. Although relatively new, sirolimus is studied as an alternative that could be safer and more efficacious. Objective: This study aims to analyze the efficacy and safety of novel sirolimus-coated balloons (SCBs) for the treatment of femoropopliteal lesions. Materials and Methods: A literature search was conducted across PubMed, Scopus, Cochrane, Science Direct, and Google Scholar databases. Five single-arm trials met the predefined eligibility criteria for inclusion and were assessed using the ROBINS-I tool. Data extraction was followed by single-arm meta-analysis in RStudio with meta package software. Major Findings: Overall, a total of 5 single-arm trials were included. During 6-month follow-ups, SCBs have proven to have a high primary patency rate (pooled: 92%) and high freedom to target lesion revascularization (TLR) rates (pooled: 96%) with no heterogeneity (I2 = 0%). In terms of safety, the pooled incidence of clinically driven—target vessel revascularization (CD-TVR) is 1%, while pooled clinically driven—target lesion revascularization (CD-TLR) rate is 2%, pooled amputation rate is 3%, and pooled incidence of mortality was 1%. During 12-month follow-ups, SCBs have high primary patency rate (pooled: 87%), high freedom to TLR rates (pooled: 96%), low amputation rate (pooled: 3%), and pooled incidence of mortality was 4%. Conclusion: Novel SCB is efficacious and safe in treating femoropopliteal lesions and thus could be a prompt alternative in treating FP lesions, although further studies are still needed. Hopefully, this method could be a treatment option for FP disease in symptomatic patients. Clinical Impact: Sirolimus-coated balloons (SCBs) offer a promising alternative to paclitaxel-coated balloons (PCBs) for femoropopliteal lesions, demonstrating high efficacy with superior primary patency and low target lesion revascularization rates. The findings suggest SCBs may mitigate safety concerns associated with PCBs, potentially reducing long-term mortality risks. For clinicians, this innovation provides a safer, effective endovascular option, enhancing patient outcomes while maintaining procedural simplicity. With further validation, SCBs could redefine the standard of care for peripheral artery disease, ensuring optimal long-term vascular health with minimal complications. © The Author(s) 2025.