Chondrocyte death relatively contributes to osteoarthritis (OA) pathogenesis. Novel agent for OA is necessary and it might be easy gain from a common citrus fruit. The shiikuwasha is a citrus fruit from Okinawa that has the potential to exert many positive effects on human health. Shiikuwasha extract (SE) displayed antioxidant properties, which were estimated through several widely used assays: DPPH, ABTS and reducing power assay. An OA-similar chondrocyte model was founded by using MIA-stimulated SW1353 cells. SE rescued the cell viability and apoptosis percentage in a dose-dependent manner. The alterations of ROS levels and ΔΨm caused by MIA were also reversed by SE. TNF-α and IL-6 were highly expressed in the culture medium only with MIA, but collagen 2 was less expressed. However, SE decreased the levels of TNF-α and IL-6, and restored collagen 2 level. Toluidine blue O staining revealed that SE blocked proteoglycan loss. The expressions of PARP, caspase 3, BAX, JAK2, p-STAT3 and STAT3 were decreased in the presence of SE, implicating the apoptosis and JAK2/STAT3 pathways participated in the effects of SE on MIA-treated SW1353 cells. Together, these findings demonstrated that SE could modulate MIA-induced apoptosis in SW1353 cells to ameliorate cartilage matrix proteins loss and inflammatory response. SE also could be regarding as bioactive or nutritional supplement for OA.