Osteoarthritis (OA) is a common disease affecting elderly individuals. Its incidence rises sharply with age, and chondrocyte apoptosis plays a vital role in its pathogenesis. Diazoxide opens mitochondrial ATP-sensitive potassium (mitoKATP) channels and exerts multiple pharmacological effects, including reductions in blood pressure and blood sugar levels. It also exerts anti-apoptotic activities, but the cellular and molecular mechanisms by which diazoxide inhibits chondrocyte apoptosis are unknown, as is whether apoptosis is related to endoplasmic reticulum stress (ERS). In the present study, we explored the mechanism underlying the chondroprotective effect of diazoxide on hydrogen peroxide (H₂O₂)-stimulated chondrocyte apoptosis in rats with surgically induced OA. A cell counting kit-8 (CCK-8) assay showed that the viability of H₂O₂-stimulated chondrocytes was enhanced in a dose-dependent manner. However, at a concentration ≥400μM, diazoxide had other, negative effects. The protective effect of diazoxide in vitro included inhibition of the ERS response and of mitochondrial dysfunction induced by H₂O₂ stimulation. These responses were related to activation of the PERK1/2 and ERK1/2 signaling pathways; the prevention of chondrocyte apoptosis; the down-regulation of caspase-3, Bax, ATF-6 and C/EBP-homologous protein (CHOP) expression; and the up-regulation of Bcl-2 and Col II. In vivo, histological and immunohistochemical analyses of caspase-3 and CHOP expression revealed that diazoxide ameliorated cartilage degeneration in a rat model of OA, as revealed by histological and immunohistochemical analyses of caspase-3 and CHOP expression. Diazoxide suppressed H₂O₂-triggered chondrocyte apoptosis, and ameliorated cartilage degeneration, by inhibiting the development of ERS.