Background: Osteoarthritis (OA) is a chronic degenerative joint disease and is the most common form of arthritis. It is the fourth leading cause of disability worldwide. Most of this disability burden is attributable to the involvement of hips or knees. Objective: The aim of the present study was to assess the clinical efficacy of Ayurvedic formulations in the management of OA knees. Materials and methods: It was an open label, multicenter, prospective, and clinical study. One hundred and twenty subjects of primary OA knees aged between 35 and 65 years, fulfilling the diagnostic criteria of the American College of Rheumatology (ACR) and showing radiological changes, were enrolled in the study. Yogaraj guggulu (500 mg) thrice a day with lukewarm water after food along with Gandharvahasta taila (6 mL) orally with lukewarm water just before bedtime and Dhanwantara taila for external application twice a day were given for 12 weeks. The assessment was done every 4 weeks. The primary outcome was assessed by seeing the change in the total Western Ontario and McMaster University osteoarthritis (WOMAC) score. Results: WOMAC score and clinical symptoms were reduced significantly from baseline to the end of the treatment. Conclusion: This study revealed the efficacy of Yogaraj guggulu along with Gandharvahasta taila and Dhanwantara taila in the management of OA knees.