The chondroprotective effect of olive leaf extract (OLE) on knee osteoarthritis (OA) was studied with STR/ort mice (n = 5). OLE was administrated with a dosage of 100 mg/kg for 8 weeks and the OA severity score of hind limb knee joints was then measured. The Mankin scores of the knee joints of the non-OA control group, OA control group and OLE-treated group were 3.50, 11.13 and 7.20, respectively. This suggests that oral OLE supplements help prevent cartilage degeneration in STR/ort mice. In vitro, the synthesis of high molecular weight hyaluronan in synovial cells (HIG-82) was increased by OLE stimulation. This suggests that OLE modulates hyaluronan metabolism in synovial cells and improves OA symptoms. Our findings indicate that OLE intake inhibits cartilage destruction by increasing high molecular weight hyaluronan and thus preventing OA progress.