Current osteoarthritis (OA) research searches for treatments that modify the course of disease progression. Autologous Protein Solution (APS) is derived from whole blood and is a unique autologous therapy that contains high concentrations of white blood cells, platelets, and concentrated plasma, providing cytokines that can target the underlying mechanisms of disease progression. The APS Kit is currently under investigation for clinical use in the USA (NCT02262364). The aim of this study was to determine if APS has disease-modifying properties in the well-characterized rat meniscal tear-induced model of OA. Thirty male athymic rats underwent surgery to induce OA by a complete tear of the medial meniscus of the right knee. Seven days later, rats were administered 50 μl intra-articular (IA) APS from a human donor or phosphate buffered saline (PBS) control. Rats were euthanized 3 weeks following treatment and knee joints were processed for histological analysis. Collagen and cartilage degeneration were decreased by APS treatment, resulting in a significantly improved total joint score in APS-treated rats compared to those treated with the PBS control. No significant variations in gait analysis, weight gain, osteophyte score, or synovitis score were observed between APS- and PBS-treated animals. There were no adverse effects of APS reported in the study. Treatment with a single IA injection of APS reduced the cartilage degeneration that characterizes the progression of OA. Further studies are necessary to determine if APS can modify OA disease progression in humans.