Osteoarthritis (OA) is an age-related arthropathy which has been considered to be associated with inflammatory damage and cartilage degradation. Liquiritigenin (LG), the main bioactive component of the rhizomes of Glycyrrhiza uralensis, has exhibited promising anti-inflammatory and anti-oxidative potential in numerous inflammatory diseases. However, the effects of LG on OA remain unclear. In this study, the therapeutic effects as well as the underlying mechanisms of LG on interleukin-1β (IL-1β)-treated rat chondrocytes had been investigated. Our results showed that LG could inhibit the IL-1β-induced expression of nitic oxide (NO) and prostaglandin E (PGE). In consist with these findings, the IL-1β-induced production of inducible nitic oxide synthase (iNOS) and cyclooxygenase-2 (COX2) could also be decreased by LG. Meanwhile, LG could suppress the IL-1β-induced upregulation of cartilage matrix catabolic enzymes including aggrecanase-2 (ADAMTS5) and matrix metalloproteinases (MMPs). Besides, the IL-1β-induced degradation of collagen II and aggrecan could be alleviated by LG. Moreover, LG prevented cartilage damage in IL-1β-treated rat cartilage explants. Mechanistically, LG functioned by inhibiting mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways activation. In general, this study reveals the anti-inflammatory properties of LG on IL-1β-treated rat chondrocytes and the possible mechanisms behind it, which may provide new ideas for OA therapy.