Aims and objectives <p>This study aims to evaluate and summarize the efficacy and safety of extracellular vesicles (EVs) and conditioned media (CM) as emerging therapeutic approaches in regenerative medicine for skin rejuvenation and lightening.</p> Methods <p>A systematic search was conducted up to September 19, 2024, using the PubMed, Scopus, and Web of Science databases. Keywords included "conditioned media," "secretome," "extracellular vesicles," “exosome,” "rejuvenation," "lightening," and others. Studies were screened based on predefined inclusion criteria, followed by data extraction. Key extracted data included study design, population characteristics (mean age and range), intervention duration, comparisons, outcomes with statistical results, and adverse effects. The statistical methods applied in individual studies were documented to assess the validity of reported improvements.</p> Results <p>This review included 19 studies with a total of 624 patients evaluating the efficacy and safety of EVs and CMs for skin lightening and rejuvenation. Among these, 21% investigated the effects of EVs, while 78% focused on CMs. The most commonly assessed skin parameters included wrinkles, pigmentation, spots, elasticity, and hydration. Various application methods were used, including topical administration, microneedling, and fractional laser therapy. Reported improvements included a 27.07% increase in skin elasticity (<i>p</i> &lt; 0.05), over 10% reduction in wrinkles (<i>p</i> &lt; 0.05), and more than 20% enhancement in hydration (<i>p</i> &lt; 0.05). No serious adverse effects were reported, with only transient minor reactions such as erythema observed.</p> Conclusion <p>EVs and CMs appear to be safe and potentially effective for skin rejuvenation and lightening. However, further high-quality studies are required to confirm long-term safety, investigate variations in efficacy based on cell sources, and optimize application techniques for clinical use.</p>