Walnut meal (WM) is rich in polyphenols which exhibit multiple therapeutic effects. The purpose of this study was to investigate the therapeutic effects of walnut meal extracts (WMP) on glycolipid metabolism and liver transcriptomics in T2DM rats. A T2DM rat model was established by using a high-fat diet combined with streptozotocin. A 5-week WMP therapy showed the effects of decreasing water intake, excretion, fasting blood glucose, fasting insulin, and insulin resistance, increasing β-cell function and insulin sensitivity index; meanwhile regulating dysfunctional lipid metabolism and reducing inflammation; improving body weight, oral glucose tolerance test and insulin sensitivity; and increasing the activities of SOD and CAT while decreasing the MDA levels in the liver and serum of T2DM rats. Moreover, 10 key differentially expressed genes were identified by RNA-seq, including Gck, RT1-Ba, Fasn, Slc13a3, Cd74, Jun, Cyp4a1, Myh7b, Plin3, and Got1, and they were highly potentially related to glycolipid metabolism. Our results suggested that WMP exhibited the anti-diabetic effect and could regulate glycolipid metabolism in T2DM rats. This finding might assist in identifying potential therapeutic targets for T2DM prevention and intervention.