Osteoarthritis (OA) is the most prevalent degenerative joint disease in both humans and companion animals, causing progressive cartilage destruction for which no curative treatment currently exists. Plasma rich in growth factors (PRGF) has shown chondroprotective effects in veterinary and preclinical models, but its efficacy is limited by the viscosity of synovial fluid and rapid degradation of growth factors within the joint. This study aimed to evaluate the effect of intra-articular co-administration of PRGF and urease-powered enzymatic nanobots on serum biomarkers of inflammation, oxidative stress, and cartilage metabolism in a rabbit (Oryctolagus cuniculus) full-depth chondral defect model (approval code: CEEA 2023-VSC-PEA-0242). Forty-one New Zealand White rabbits were allocated to a Control group (PRGF alone; n = 9 evaluable) or a Nanobots group (PRGF + nanobots; n = 24 evaluable). Twelve serum biomarkers were measured at baseline and days 28, 56, and 84. The Nanobots group showed markedly elevated serum hyaluronic acid at all timepoints (p < 0.006), significantly lower type II collagen cleavage neoepitope at day 28 (p = 0.018), persistently lower ferric reducing ability of plasma (p < 0.003), and higher C-reactive protein at days 56 and 84 (p < 0.035). These results provide preliminary in vivo evidence that urease-powered nanobots produce a distinct biomarker profile when combined with PRGF in a rabbit chondral defect model, with potential translational relevance for veterinary orthopedic therapy.