Background: Osteoarthritis is a disease that occurs due to articular cartilage degeneration. It commonly manifests as fluctuating joint pain, stiffness, and locomotor restriction. In the past decade, researchers have discovered that mesenchymal stem cells (MSCs) could potentially treat osteoarthritis. However, improper administration of MSCs may cause serious adverse events, and the process can be costly. Recent findings suggest that MSC secretomes can reverse the damage caused by osteoarthritis. This study aims to systematically report the Methods: We searched PubMed, the Cochrane Library, and the Directory of Open Access Journals (DOAJ) for open-access experimental articles in English containing primary data regarding Results: Secretome was significantly able to preserve mechanical tensile and compressive strength, increase chondrocyte survival and proliferation, promote autophagy of senescent and damaged cells, reduce fibrosis and joint stiffness, reduce joint inflammation, inhibit pathologic processes following inflammation, and reduce the expression of pain-associated genes in osteoarthritic joints. Experimental studies reported that joints receiving secretome therapy demonstrated histologic and functional recovery to levels comparable to healthy joints. Conclusions: Secretome therapy represents a novel treatment modality with the potential to provide a definitive and comprehensive solution for osteoarthritis. Further research regarding the safety and efficacy of secretome therapy in human joints is needed to facilitate its clinical application as soon as possible.