Background Lameness is one of the major causes of reduced physical performance and early retirement in working horses. TamaFlex™ (NXT15906F6) is a standardized synergistic anti‐inflammatory botanical formulation containing Tamarindus indica seed extract and Curcuma longa rhizome extract at a 2:1 ratio. Methods We conducted a 12‐week single‐center, randomized, blinded, placebo‐controlled trial demonstrating the efficacy of NXT15906F6 in horses with lameness grade 2–4 on the American Association of Equine Practitioners (AAEP) scale. Twenty‐two lame horses were supplemented with NXT15906F6 (2.5 gram/day) or placebo over a period of 84 days. Improvement in lameness over placebo was the primary endpoint, and changes in the levels of rheumatoid factor (RF), anti‐nuclear antibody (ANA), and anti‐cyclic citrullinated peptide (ACC‐peptide) in serum, and pro‐inflammatory cytokines including interleukin (IL‐1β and IL‐6), tumor necrosis factor‐α (TNF‐α) and prostaglandin‐E2 (PGE2) in serum and synovial fluid were the secondary endpoints. Results NXT15906F6 exhibited significant relief from lameness in a time‐dependent manner. NXT15906F6 also reduced levels of ANA, PGE2, IL‐1β, TNF‐α and IL‐6. Moreover, NXT15906F6 supplementation is safe and tolerable in alleviating joint pain in lame horses, and protects the joints from further degradation by reducing pro‐inflammatory mediators. Conclusion NXT15906F6 significantly reduces the lameness during walking and trotting, leading to an improvement in their joint flexibility, health, and working performances.