Knee pain is commonly seen in orthopedic and rehabilitation outpatient clinical settings. Patients with knee osteoarthritis (OA) are often complicated with joint soreness, swelling, weakness, and pain. These complaints are often caused by the excessive amount of synovial fluid (SF) accumulated in the bursae around the knee joint. This study was aimed to evaluate the effectiveness of platelet rich plasma (PRP) in treating patients with minor to moderate knee osteoarthritis (OA) combined with supra-patellar bursitis using a proteomic approach and clinical evaluation tool. In this study, 24 elderly patients with minor to moderate knee OA combined with supra-patellar bursitis were recruited. Musculoskeletal ultrasound was used for accurate needle placement for the aspiration of SF followed by subsequent PRP injections. Three monthly PRP injections were performed to the affected knees for a total of 3 months. Approximately after the 2nd PRP injection, significant decreases in SF total protein concentrations, volumes, and Lequesne index values were observed. SF proteins associated with chelation and anti-aging physiological functions such as matrilin, transthyretin, and complement 5 increased at least 2-fold in concentrations. Proteins associated with inflammation, such as apolipoprotein A-I, haptoglobin, immunoglobulin kappa chain, transferrin, and matrix metalloproteinase decreased at least 2-fold in concentrations. Therefore, at least two monthly PRP injections may be beneficial for treating patients with minor to moderate knee OA combined with supra-patellar bursitis.