Dibutyl phthalate (DBP) is widely used as plasticizer in numerous kinds of products and migrate into the human bodies through food plastic packaging, posing potential health hazards to organisms. Accumulating experimental evidence has shown that DBP causes multiple organ damage, such as aggravate the allergic airway inflammation and mediate oxidative stress induces splenic injury in mice. However, the specific toxicity and underlying mechanism of DBP-induced knee joint injury remains poorly understood, especially any association between DBP exposure with pathological progression of osteoarthritis (OA) remain elusive. In our study, mice were treated by intragastric administration of DBP (50 mg/kg or 250 mg/kg) five times per week for 4 and 8 weeks, and results suggested that DBP exposure accelerated the regression of OA. Specifically, DBP augmented cartilage matrix degradation by decreasing Col2, Aggrecan and increasing Mmp3, Mmp13 and Adamts5. Further analysis revealed that DBP significantly inhibited chondrocytes proliferation, promoted apoptosis and pyroptosis of chondrocytes, augmented sensory nerve ingrowth in subchondral bone. Mechanistical analysis revealed that DBP stimulated NF-κB signaling by increasing I-κBα phosphorylation and subsequent p65 nuclear translocation. The data suggest that DBP inhibits chondrocyte proliferation, promotes apoptosis and pyroptosis of chondrocytes to accelerate the progression of OA by activating NF-κB signaling. In summary, our data provides a new insight into the impacts of the DBP-induced chondrocyte toxicity as well as the safety evaluation of DBP.