The inhibitory effect of a Curdrania tricuspidata leaf extract (CTL) on osteoarthritis (OA) was investigated in primary cultured rat cartilage chondrocytes. To identify the effect of the CTL following hydrogen peroxide (H2O2) (1.5 mM, 2 hr) treatment, cell survival was measured using the methylthiazol tetrazolium (MTT) assay. Cell survival after H2O2 treatment was elevated by the CTL at a concentration of 400 μg/mL. In vitro studies with primary chondrocytes showed that the CTL decreased and normalized the production of the arthritis factors, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). The cytokine level was significantly decreased following a 200 μg/mL dose of CTL treatment. Furthermore, the CTL treated chondrocyte exhibited a decrease in lipopolysaccharide (LPS) induced NO synthesis, especially at a concentration of 200 μg/mL. The genetic expression of cyclooxygenase-2 (COX-2), nuclear transcription factor κB (NF-κB), matrix metalloproteinases (MMPs), collagen, and aggrecan were determined using the real-time polymerase chain reaction (PCR) method. CTL treatment significantly decreased and normalized the production of the proinflammatory factors (NF-κB and COX-2) at a concentration of 200 μg/mL. For MMPs (MMP-3, MMP-13), known as catabolic factors, gene expression was significantly inhibited by treatment with the CTL, especially with a 200 and 400 μg/mL dose. In addition, for type II collagen and aggrecan, known as anabolic factors, the gene expression was significantly increased following treatment with the CTL. In conclusion, the CTL was able to inhibit articular cartilage degeneration by preventing extracellular matrix degradation and chondrocyte injury. Therefore, the CTL may be a potential therapeutic agent for degenerative OA.