Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation, inflammation, and loss of joint function. While mesenchymal stem cells (MSCs) hold promise for OA therapy due to their regenerative and immunomodulatory properties, challenges such as poor survival, suboptimal differentiation, and an inflammatory microenvironment limit their clinical efficacy. Natural products, including curcumin, resveratrol, quercetin, and epigallocatechin gallate (EGCG), have emerged as a complementary strategy to enhance MSC-based therapies for OA. These bioactive compounds modulate key inflammatory pathways (NF-κB, MAPK, PI3K/AKT), reduce oxidative stress, and promote chondrogenic differentiation of MSCs. Preclinical studies demonstrate the synergistic effects of MSCs and natural products in attenuating inflammation, enhancing cartilage repair, and improving joint function in OA models. However, clinical translation is hindered by challenges in bioavailability, standardization of MSC protocols, and regulatory hurdles. Future research should focus on optimizing delivery systems, conducting large-scale randomized controlled trials, and establishing personalized treatment strategies based on patient biomarkers. By addressing these challenges, the integration of natural products into MSC-based therapies could revolutionize OA treatment, offering a disease-modifying approach for millions of patients worldwide.