A high-fat diet (HFD) promotes tissue inflammation, oxidative stress and insulin resistance (IR), thereby contributing to the development of obesity and diabetes. Anthocyanins from Lycium ruthenicum (AC) have demonstrated anti-obesity effects and modulated IR. To investigate the mechanism by which AC attenuates the adverse effects of consuming a HFD, C57BL/6J mice were fed a HFD supplemented with AC or a control diet without AC for 12 weeks. AC supplementation decreased the amount of weight gain, hepatic lipid, and sequentially improved dyslipidemia, inflammation, oxidative stress, and IR in HFD-fed mice. Molecular data revealed that AC inhibited hepatic inflammation by reducing TLR4/NF-κB/JNK in the liver tissues and ameliorated oxidative stress by activating the Nrf2/HO-1/NQO1 pathway. Thus, AC might activate IRS-1/AKT and prevent HFD-induced gluconeogenesis and IR by ameliorating inflammation and oxidative stress. Modulation of inflammation and oxidative stress with AC may represent a promising target for the treatment of IR and provide insight into the mechanism by which AC protects against obesity.