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Simple Summary: Osteoarthritis is an incurable chronic disease. For this reason, new therapies are constantly emerging to improve clinical signs and the quality of life of our pets. Chondroitin sulfate, glucosamine and hyaluronic acid have been proven effective and are the most widely used in many formulations. In the present study, adding native type II collagen to the combination of chondroitin sulfate, glucosamine and hyaluronic acid showed improvements on osteoarthritis progression in an experimental model of osteoarthritis induced by transection of the cranial cruciate ligament of the knee in New Zealand white rabbits. Disease progression was monitored at different time points using magnetic resonance imaging biomarkers, measurement of hyaluronic acid in synovial fluid, and macroscopic and microscopic evaluations of cartilage, synovial membrane and subchondral bone. Overall, our results showed that adding native type II collagen to a combination of glycosaminoglycans allows a significantly slower osteoarthritis progression, compared to glycosaminoglycans alone. A prospective, experimental, randomized, double blinded study was designed to evaluate the effects of glycosaminoglycans, with or without native type II collagen (NC), in an osteoarthritis model induced by cranial cruciate ligament transection. The following compounds were tested: chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), hyaluronic acid (HA) and NC. Fifty-four female 12-week-old New Zealand rabbits were classified into three groups: CTR (control–no treatment), CGH (CS + GlHCl + HA) and CGH-NC (CS + GlHCl + HA + NC). Each group was subdivided into three subgroups according to survival times of 24, 56 and 84 days. Over time, all rabbits developed degenerative changes associated with osteoarthritis. CGH-NC showed significantly improved values on macroscopic evaluation, compared to CTR and CGH. Microscopically, significantly better results were seen with CGH and CGH-NC, compared to CTR, and synovial membrane values were significantly better with CGH-NC compared to CGH. A significant improvement in magnetic resonance imaging biomarkers was also observed with CGH-NC in cartilage transversal relaxation time (T2) and subchondral bone D2D fractal dimension in the lateral condyle. In conclusion, our results show beneficial effects on joint health of CGH and CGH-NC and also supports that adding NC to CGH results in even greater efficacy. [ABSTRACT FROM AUTHOR]