We evaluated the chondroprotective and anti-nociceptive effects of caffeoylquinic acid (CA) in a rat osteoarthritis (OA) model. Monosodium iodoacetate was injected intra-articularly in the rats to produce OA. The rats were divided into three groups: control, OA group, which received vehicle, and the CA-treated group, which received CA (50mg/kg, p.o.) for 14days. At the end of the protocol, pain was estimated by observing the paw withdrawal threshold and latency. Degeneration of cartilage was assessed through histomorphological and microscopical examination of joints. Levels of mRNA were estimated in interleukin-1β (IL-1β)- and IL-6-stimulated chondrocytes. The results suggested that treatment with CA significantly attenuated the degeneration of cartilage and pain in OA rats. The histopathology study revealed that the number of osteoclast cells was reduced significantly in the CA-treated group. Moreover, expression levels of inducible nitric oxide synthase (iNOS), nitrotyrosine, IL-6, and IL-1β were decreased significantly in the CA-treated group versus the OA group. Additionally, CA reduced the expression of metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), matrix metalloproteinase-13 (MMP-13), and MMP-3, and tissue inhibitor of metalloproteinases-1 (TIMP-1) was enhanced in IL-1β-stimulated chondrocytes. The c-jun N-terminal kinase (JNK) level was reduced significantly (p<0.01) in the CA-treated group. In conclusion, treatment with CA protected against degradation of articular cartilage in the OA rat by balancing the homeostasis of cartilage extracellular matrix (CEM) and by reducing oxidative stress. CA affects OA on the basis of its strong anti-inflammatory and anti-oxidant properties.