Matrine is an active ingredient in traditional Chinese medicine that has been shown to be effective in treating bone disorders. The anti-osteoarthritis (OA) effects of matrine were assessed using both in in vitro and in vivo systems, and the mechanisms underlying the effects were investigated by focusing on the activity of miR-29b-3p/PGRN axis. The miR was chosen as potential target for matrine after chondrocytes were treated with both IL-1? and matrine. Changes in cell viability, cell apoptosis, inflammation, and miR-29b-3p/PGRN axis were detected. In vitro assays results were validated using collagen-induced arthritis (CIA) rat models. Incubation with IL-1? reduced cell viability, induced cell apoptosis, and inhibited production of cytokines in chondrocytes, which was associated with the up-regulation of miR-29b-3p and down-regulation of PGRN. In CIA rats, matrine reduced bone destruction and weight loss in a dose-dependent manner. Matrine also reduced the systemic levels of cytokines. At the molecular level, matrine inhibited the expression of miR-29b-3p while increasing the expression of PGRN. The findings outlined in the current study showed that matrine exerted its anti-OA effects by modulating the miR-29b-3p/PGRN axis.