Introduction: Recent studies have shown the regenerative potency of extracellular vesicle Mesenchymal Stem Cells (EV-MSCs) due to their non-cellular, low immunogenic profile and chondrogenic potency. Osteoarthritis of the knee (KOA) is one of the most prevalent degenerative diseases caused by progressive cartilage degeneration; to date, there is no cure. This study aims to evaluate the effect of intra-articular exosome adipose-derived mesenchymal stem cell (AD)-MSC injection in an ovine low-grade OA model radiologically and histologically. Materials and Methods: A total of 14 male Ovis aries sheep with low-grade OA were divided into seven treatment groups: control (NaCl), 1x exosome, 2x exosome, 3x exosome, 1x hyaluronic acid (HA), 2x HA, and 3x HA injection groups. Each group that received multiple injections was injected at a one-week interval. After six weeks of intervention, a radiographic examination was performed, and the ovine was sacrificed. After the sacrifice, histological analysis was performed. Results: Radiographic evaluation showed the slowest progression of OA in the 3x exosome group, followed by 2x exosome, 1x exosome, 3x HA, 2x HA, 1x HA, and control group consecutively with delta progression (0.5; 1; 1; 1; 1.5; 1.5; 2). Meanwhile, histological analysis showed that the 3x exosome group retained proteoglycan content in the ovine osteoarthritis model cartilage matrix. Conclusion: 3x exosome injection with a one-week interval showed the slowest progression and highest matrix retainment in the ovine low-grade OA model. Further studies with larger samples should be performed to evaluate the statistical result of these differences. © 2025 Universiti Putra Malaysia Press. All rights reserved.