OBJECTIVE: To evaluate the effects of TRB-N0224, a chemically modified curcumin (CMC) with zinc binding properties and improved pharmacokinetics, in a rabbit anterior cruciate ligament (ACL) transection injury-induced model of osteoarthritis (OA). DESIGN: Thirty-eight skeletally mature New Zealand white rabbits were studied in 4 groups: a sham with arthrotomy ( = 6), control with ACL transection ( = 6), and 2 treatment groups with ACL transection and administration of TRB-N0224 at low (25 mg/kg/day) ( = 13) and high (50 mg/kg/day) ( = 13) doses. After euthanization at 12 weeks, outcomes were measured by post-necropsy gross morphology, biomechanics, and cartilage and synovium histology. Rabbit blood ELISA quantified cytokine and matrix metalloproteinase (MMP) concentrations at 0, 4, 8, and 12 weeks. RESULTS: Both treatment doses had fewer distal femoral condyle erosive defects than the control; the low dose demonstrated a mean 78% decrease ( < 0.01). Histologically, the low- and high-dose treatment groups had fewer cartilage pathologic changes and less severe synovitis than the control. CMC alone did not have a major effect on the biomechanics of healthy cartilage or cartilage in the ACL transection model, as demonstrated in 5 of the 6 measured properties/regions ( < 0.05). ELISA results suggested that the key mediators of OA, (interleukin) IL-1β, IL-6, TNFα (tumor necrosis factor-α), MMP-9, and MMP-13, had decreased concentrations with TRB-N0224 treatment at different time points between weeks 4 to 12 ( < 0.05). CONCLUSIONS: In the pathogenesis of OA, an imbalance exists between catabolic and anabolic mediators. These results suggest the potential of TRB-N0224 to modulate MMP and cytokine levels, slowing the macroscopic and histopathological progression of OA.