Osteoarthritis (OA) is the most commonly observed arthritic disease causing severe pain and impairing patient's quality of life. This study aimed to investigate and compare the effect of Elaeagnus angustifolia extract and quercetin on the mouse model of knee osteoarthritis (OA). Sixty Balb-C mice were used to establish the monosodium iodoacetate (MIA) model of OA. Then, they were randomized into untreated OA group (normal nutrition), E. angustifolia extract-treated group (32 mg/kg by gavage), quercetin-treated group (20 mg/kg by gavage) and ibuprofen- treated group (20 mg/kg). Fifteen mice with no MIA treatment were considered as the normal controls. The mice were treated for 28 days. The histopathological analysis was performed on knee joints. Expression levels of matrix metalloproteinase 3 and 13 (MMP-1 and MMP-13) in serum were assessed in addition. Histopathological study indicated that in the quercetin-treated group, the thickness of femur and tibia were significantly increased (P < 0.05). Among groups treated by E. angustifolia extract, quercetin and ibuprofen, the concentration of MMP-3 was 5.47 ± 1.75 ng/ml, 4.38 ± 1.78 ng/ml and 4.86 ± 1.40 ng/ml, respectively. The level of MMP-13 in sera was 3.32 ± 1.64 ng/ml, 2.67 ± 1.73 ng/ml and 5.31 ± 1.68 ng/ml in the same order (P < 0.05). The results of this study suggest that the quercetin was useful in the reduction of symptoms of OA and raised the improvement of damaged cartilage. Hence, it can be a beneficial medical supplement in OA treatment. Besides, E. angustifolia extract and quercetin significantly reduced the serum MMP-3 and MMP-13 concentrations. It could be one of the mechanisms through that E. angustifolia plays a role in remission of OA.