Osteoarthritis (OA) is a chronically progressive degenerative arthropathy characterized by the loss of cartilage, changes in subchondral architecture, and ongoing inflammation resulting in reduced mobility and pain. This study assessed the treatment potential of a combination of chondroitin and glucosamine enriched with Curcumin C3 Complex (C3GC) in modulating the pathophysiological features in mouse models with surgically induced OA and in dogs with naturally occurring OA. A cohort of 24 male C57BL/6 mice aged 3 months old were surgically destabilized with medial meniscus (DMM) to cause osteoarthritis. These animals underwent a nutritional intervention with C3GC or with GC over a course of 8 weeks. In order to evaluate cartilage health and subchondral bone structure, we carried out a combination of behavioral tests, micro-computed tomography (micro-CT), and histopathological examinations. In addition, a cohort of 12 OA-diagnosed retired police dogs were administered C3GC supplements or conventional care over a course of 30 days, with pain measurement and serum concentrations of MMP-3 and TNF-α determined before and after treatment. According to our findings, the administration of C3GC was determined to preserve subchondral microarchitectural structure integrity ( < 0.05) and resulted in better motor function in comparison with GC. In animals taking nutritional supplements, the OARSI scores of joint tissue sections were reduced, with the medial tibial plateau OARSI score being particularly low in the C3GC group ( < 0.0001). In dogs, treatment with C3GC resulted in a 24.5% reduction in serum MMP-3 levels ( < 0.01), and there was also a 20.8% decrease in serum TNF-α levels ( < 0.05), along with a decrease in subjective pain assessment. The results are in support of the chondroprotective, anti-inflammatory, and analgesic properties of C3GC and justify future research on the potential utility of C3GC in treating osteoarthritis.