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Exosomes are secreted tiny organelles that are single-membrane enclosed and can perform a broad spectrum of functions upon release, such as the reorganization of extracellular matrix and communication with other cells through the release of signals and chemicals, which play an important role in development, immunity, tissue homeostasis, cancer, and neurodegenerative diseases, among other aspects of human health and disease. This systematic review aimed to evaluate the clinical efficacy and safety of exosome-based therapies for skin rejuvenation in human populations and to identify gaps in the existing evidence. A methodological literature search was performed in databases such as PubMed, Scopus, Cochrane Library, and Web of Science with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Clinical experiments that were conducted on humans to assess exosome-based interventions to rejuvenate the aesthetic skin were encompassed. The process of study selection, data extraction, and quality appraisal was done independently by two reviewers. Synthesis of results was narrative, since there was methodological heterogeneity. A total of 19 studies were included, but most of them were not randomized. There was an association between exosome-based interventions and skin hydration, elasticity, wrinkles, pores, pigmentation, and overall appearance improvement in the short term. The majority of the studies reported a positive safety profile of topical application, with the exception of individual reports of risks with off-label injectable use. Exosome-based therapies showed encouraging early clinical effects of skin rejuvenation, and the existing evidence is marred by heterogeneity and lack of follow-up. Rigorous randomized trials and standardized reporting are required.