Objective: To study the inhibitory effect of α7 nicotinic acetylcholine receptor (α7-nAChRs) on chondrocyte apoptosis, providing a new idea and research strategy for the clinical treatment and study of osteoarthritis (OA). Methods: Mice were randomly divided into the following groups: control group, MIA (monosodium iodoacetate) treatment alone group, MIA + Nic (Nicotine 0.5 mg/kg or 1 mg/kg) treatment group and MIA + Nic + MLA (Methyllycaconitine, MLA) treatment group. A mouse model of OA induced by injection of MIA was used to study the effects of nicotine on joint pain, cartilage degeneration and chondrocyte apoptosis. Mechanical withdrawal sensitivity was detected using Von Frey hairs at 7, 14, and 21 days after MIA injection. Cartilage degeneration was assessed using Mankin score and aggrecan loss score at 21 days after injection. Apoptosis of articular cartilage was determined by terminal deoxynucleotidyl transferase dUTP Nick end labelling (TUNEL) staining. Meanwhile, western blotting was used to detect the expression of apoptosis-related proteins Bcl-2, Bax, cleaved caspas-9 and caspase-9. Results: MIA injection induced rapid pain-like responses that persisted for 3 weeks in mice. Toluidine blue staining and saffron fast green staining revealed loss of the hypertrophic chondrocyte layer and a decrease in cellularity in the MIA group. TUNEL fluorescent staining revealed increasement of chondrocyte apoptosis in knee joint of mice subjected to MIA injection. 1.0 mg/kg Nic treatment reduced pain behavior (P < 0.05), cartilage degeneration (P < 0.05), and chondrocyte apoptosis (P < 0.05). In addition, nicotine treatment reduced MIA-induced down-regulation of Bcl-2, up-regulation of Bax and cleaved caspase-9/caspase-9 ratio levels (P < 0.05). The benefit of nicotine was abolished by a selective α7 nicotinic receptor blocker MLA in vivo. Conclusion: The activation of α7-nAChRs has a protective effect on cartilage damage in OA model mice and exerts an anti-chondrocyte apoptosis effect by inhibiting the mitochondrial apoptotic pathway.