Osteoarthritis (OA) is a slow, chronic disease characterized by the focal deterioration and abrasion of articular cartilage. Leptin may play an important role in the pathophysiology of OA. Exercise and glucosamine sulfate therapy is one of the most commonly used in patients with knee OA. The goals of the present study are performed to investigate whether 12-week strength training program and glucosamine sulfate have an effect on serum leptin levels in knee OA and the relationship between leptin, clinical parameters, and radiographic severity of knee OA. Thirty-seven women with the diagnosis of knee OA were enrolled in the study. Patients were randomized into two groups. Group I (n = 19) received an exercise program, while group II (n = 18) received glucosamine sulfate (1,500 mg/day) in addition to the exercise therapy. Both groups were treated for 12 weeks. Leptin level was assessed at baseline and after 12 weeks. The concentration of leptin was measured by ELISA. The patients were evaluated regarding pain, disability, functional performance, and muscle strength. Both groups showed significant improvements in leptin levels, pain, disability, muscle strength, and functional performance with no statistically significant difference between the groups after the therapy. At basal time, plasma leptin levels were significantly correlated with body mass index and duration of disease, but no significant correlation was found with patient age, pain, disability, functional performance, muscle strength, and radiographic severity of knee OA. The results of this preliminary study revealed that exercise alone was adequate to prevent structural changes relieving the symptoms of OA. We also found that exercise alone could affect serum plasma levels of the leptin, important mediators of cartilage metabolism. Decreases in serum leptin may be one mechanism by which cartilage metabolism affects physical function and symptoms in OA patients.