NXT15906F6 (TamaFlex™) is a proprietary blend containing standardized Tamarindus indica seeds and Curcuma longa rhizome extracts. Earlier, NXT15906F6 supplementation demonstrated reduced knee joint pain and improved musculoskeletal functions in healthy and knee osteoarthritis (KOA) subjects. The present randomized, double-blind, placebo-controlled study was focused on validating the clinical efficacy of NXT15906F6 in a larger number of subjects with KOA. Male and female subjects (age: 40-70 years; body mass index [BMI]: 20-29 kg/m2] were randomized into three groups receiving placebo (n = 50), NXT15906F6 (n = 50) or a blend of C. longa and Boswellia serrata extracts (CLBS) (n = 50). Subjects consumed 250 mg NXT15906F6, 1,000 mg CLBS or a matched placebo daily after breakfast over a period of 30 consecutive days. The primary efficacy outcome was the improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and the secondary efficacy measures included various tests on joint pain and musculoskeletal functions and evaluations ofserum high-sensitivity C-reactive protein (hs-CRP) and a cartilage degradation marker, C-terminal telopeptide of type II collagen in urine (uCTX-II). NXT15906F6 significantly (P < 0.001) reduced the WOMAC scores and improved musculoskeletal function scores in the participants as compared with baseline and placebo. NXT15906F6 participants reduced knee pain and improved musculoskeletal functions as early as day 5 of supplementation. In contrast, CLBS supplementation failed to show early efficacies in pain and functional scores, except for 30s-CST and primary knee flexion. The NXT1506F6-supplemented participants significantly reduced serum hs-CRP and uCTX-II levels from baseline and as compared with the placebo. Both supplementations did not alter the subjects' clinical chemistry, hematology, and vital parameters. The anti-inflammatory botanical composition NXT15906F6 supplementation mitigated joint pain and improved musculoskeletal functions and joint motility in KOA subjects. This botanical composition was also well-tolerated by the volunteers.