Introduction: The treatment of osteoarthritis (OA), a disease affecting the majority of the elderly population, involves the alleviation of symptoms, such as pain and stiffness, and the reduction of inflammation.Objectives: To evaluate the efficacy of Elaeagnus Angustifolia (EA) extract tablets in the treatment of patients with osteoarthritis of the knee, compared with acetaminophen and a control group administered placebo tablets.Material and Methods: In this study, 120 patients with OA of the knee and with moderate to severe pain, with no significant concomitant disorders, and with matching age, sex, BMI, and Kellgren-Lawrence grades were studied in a randomized placebo-controlled double-blind 7-week trial. The trial consisted of a 2-week washout period followed by three different treatment plans, with 40 patients receiving Elaeagnus angustifolia extract, 40 patients receiving a placebo, and 40 patients administered acetaminophen, each with a dosage of 2 tablets per day. Patients with severe pain, permitted using naproxen as rescue medication throughout the study. The evaluation of the results consisted of visual analogue scale (VAS) pain assessment, Lequesne’s Pain-Function Index (LPFI), and patient and physician global Assessment of efficacy and tolerability by patient and physician.Results: 115 patients were evaluated for 7 weeks; 38 patients received EA; 37 received acetaminophen; 40 received placebo. The mean±SD LPFI score decreased from 9.3±2.6 to 6.7±3.1 in the EA group and from 10.4±2.8 to 8.6±2.9 in the acetaminophen group and from 9.4±2.9 to 8.3±2.9 in the placebo group (P<0.001). Pain decreased from 40.8±17.8 to 23.2±15.4 in the EA group and from 37.4±18.6 to 27.8±19.6 in the acetaminophen group, and from 42.6±13.5 to 41.6±12.7 in the placebo group at week 7 (P<0.001). For patient and physician global assessment, improvements from baseline in EA groups were superior to the acetaminophen and placebo groups (P<0.001). No clinically or statistically significant differences were seen in adverse events or tolerability among the study groups.Conclusion: This study showed that Elaeagnus angustifolia extract, a new herbal remedy, provides significant efficacy over a cetaminophen and placebo in treatment of OA of the knee.