The chondroprotective effects of dopamine on osteoarthritis were possibly related to its ability to inhibit the NF-κB and JAK2/STAT3 signaling pathways. Display omitted •Dopamine suppressed matrix-degrading protease production in OA chondrocytes.•Dopamine reduced the activation of the NF-κB pathway induced by IL-1β.•Dopamine exhibits chondroprotective effects by inhibiting the JAK2/STAT3 pathway activation.•Dopamine prevented the development of osteoarthritis in a mouse model. The progressive loss of cartilage matrix and the breakdown of articular cartilage induced by inflammation play an essential role in osteoarthritis (OA) pathogenesis. Dopamine (DA) is a critical neurotransmitter that is not only involved in controlling exercise, emotion, cognition and neuroendocrine activity but also has anti-inflammatory effects. This study aimed to investigate the effects of DA on OA in vitro and in vivo. OA progression was evaluated in a mouse model with surgically induced destabilization of the medial meniscus. Cartilage degradation and OA were analyzed using Safranin O/Fast Green staining. Additionally, qRT-PCR and Western blotting were applied to detect catabolic and anabolic factors involved in cartilage degeneration and underlying mechanisms in OA chondrocytes treated with Interleukin-1β. In vitro, DA treatment inhibited the production of inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13, while increasing type II collagen and glycosaminoglycan content. Mechanistically, DA reversed IL-1β-treated nuclear factor-kappa B activation and JAK2/STAT3 phosphorylation. Furthermore, DA suppressed the degradation of cartilage matrix and reduced Osteoarthritis Research Society International scores in the surgically induced OA models. DA may be a novel therapeutic agent for OA treatment.