The aim of this study is to evaluate the feasibility and usefulness of the human umbilical cord mesenchymal stem cells (hUC-MSCs) and hyaluronan acid (HA) combination to attenuate osteoarthritis progression in the knee while simultaneously providing some insights on the mitigation mechanism. In vitro, the effect of hUC-MSCs with HA treatment on chondrocyte cell viability and the cytokine profile were analyzed. Additionally, the antioxidation capability of hUC-MSCs-CM (conditioned medium) with HA towards H₂O₂-induced chondrocyte cell damage was evaluated. The HA addition increased the hUC-MSC antioxidation capability and cytokine secretion, such as Dickkopf-related protein 1 (DKK-1) and hepatocyte growth factor (HGF), while no adverse effect on the cell viability was observed. In vivo, the intra-articular injection of hUC-MSCs with HA to a mono-iodoacetate (MIA)-induced knee osteoarthritis (KOA) rat model was performed and investigated. Attenuation of the KOA progression in the MIA-damaged rat model was seen best in hUC-MSCs with a HA combination compared to the vehicle control or each individual element. Combining hUC-MSCs and HA resulted in a synergistic effect, such as increasing the cell therapeutic capability while incurring no observable adverse effects. Therefore, this combinatorial therapy is feasible and has promising potential to ameliorate KOA progression.