Objective: To investigate the protective effect of glycyrrhizin on articular cartilage in post-traumatic osteoarthritis (PTOA) and the related mechanism thereof. Methods: Twenty-four Sprague Dawley rats were randomly divided into sham, PTOA, 20 mg•kg -1 , and 50 mg•kg -1 glycyrrhizin groups, with six rats in each group. The PTOA rat model was established by anterior cruciate ligament transection, and the rats were intragastrically administered with 20 mg•kg -1 and 50 mg•kg -1 glycyrrhizin. The pain indexes, pathology, inflammation, apoptosis, extracellular matrix, and toll-like receptor 4/Nuclear factor kappa B (TLR4/NF-κB) signaling pathway proteins were detected after treatment. Results: Compared with the sham group, the pain indexes, proteoglycan content, and the expression of Bcl-2, collagen II, and aggrecan significantly decreased, whereas the Mankin's and Osteoarthritis Research Society International (OARSI) scores, levels of inflammatory factors, and expression of Bax, Caspase-3, MMP-3, MMP-13, ADAMTS5, TLR4, Myd88, and p-p65 were significantly increased in the PTOA group (P<0.05). After 20 mg•kg -1 and 50 mg•kg -1 glycyrrhizin treatment, the proteoglycan content and expression of Bcl-2, collagen II, and aggrecan were significantly increased, whereas the Mankin's and OARSI scores, levels of inflammatory factors, and expression of Bax, Caspase-3, MMP-3, MMP-13, ADAMTS5, TLR4, Myd88, and p-p65 were significantly decreased (P<0.05). The improvement was more significant in the 50 mg•kg -1 glycyrrhizin group (P<0.05). Conclusion: Glycyrrhizin could inhibit inflammation and articular cartilage degeneration by inhibiting the activation of the TLR4/NF-κB signaling pathway, thereby improving the function of the knee joint in PTOA modeled rats.