Curcuma longa Linn. is widely used for the treatment of disorders associated with inflammation and was evaluated for its safety and efficacy in the treatment of painful knee osteoarthritis (OA). This was a randomized, single blind, placebo-controlled trial. Total of 120 patients (37 males and 83 females) with primary knee OA received either placebo (400 mg twice daily) or NR-INF-02 (500 mg twice daily) or glucosamine sulphate (GS) (750 mg twice daily) alone or combination of NR-INF-02 and GS for 42 days. The efficacy was assessed during treatment period, on day 21 and day 42. The decrease in severity of pain symptom and function of affected knee as primary efficacy outcome measure was assessed by Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, respectively. The clinical examination of affected joint was measured by an orthopaedic specialist and using a Clinician Global Impression Change (CGIC) scale. The analysis of post-treatment scores following administration of NR-INF-02 using VAS, WOMAC, and CGIC at each clinical visit showed significant decrease (p < 0.05) compared to placebo. NR-INF-02 treated group showed a significant (p < 0.01) decrease in use of rescue medication, along with clinical and subjective improvement compared to placebo. The tolerability and acceptability profile of NR-INF-02 was better during the trial period. The study demonstrates safety and efficacy of NR-INF-02 as a useful treatment option for patients with primary painful knee OA.