<p>Osteoarthritis is a prevalent condition among middle-aged and elderly populations characterized primarily by the progressive degeneration of articular cartilage. Despite advances in medical technology, the complexity of osteoarthritis pathogenesis presents significant challenges in halting or reversing cartilage degradation. Recently, mesenchymal stem cells and their secretome have emerged as promising regenerative therapies for osteoarthritis. Mesenchymal stem cells not only differentiate into chondrocytes to repair cartilage defects but also maintain chondrocyte homeostasis by interacting with existing chondrocytes and modulating synovial inflammation. Additionally, the proteins and bioactive molecules contained within the mesenchymal stem cell secretome offer multifaceted therapeutic benefits. However, challenges such as the limited survival and integration of transplanted mesenchymal stem cells, potential for unwanted differentiation, and variable efficacy of the secretome persist. Hydrogels, which mimic the chemical and mechanical properties of the extracellular matrix, are frequently utilized as carriers for mesenchymal stem cells and their secretome in osteoarthritis treatments. This review explores the current applications of mesenchymal stem cells and their secretome in osteoarthritis therapy, proposing innovative strategies to overcome these existing treatment limitations.</p>