Evodiamine (EVO) is an alkaloid extracted from Evodia rutaecarpa and has various pharmacological activities, including hypolipidemic, anti-inflammatory, anti-infective, and antitumor effects. However, the therapeutic effects of EVO on type 2 diabetes mellitus (T2DM) and the possible mechanisms remain unknown. In this study, we used a T2DM rat model using a high-fat diet (HFD) combined with streptozotocin (STZ) injections followed by treatment with EVO. First, we evaluated the therapeutic effects of EVO on T2DM rats, following which we evaluated the anti-inflammatory and anti-oxidative effects of EVO on T2DM rats. Finally, we analyzed the metabolic regulatory mechanism of EVO in T2DM rats using an untargeted metabolomics approach. The results showed that EVO treatment alleviated the hyperglycemia, hyperlipidemia, insulin resistance (IR), and pathological changes of the liver, pancreas and kidneys in T2DM rats. Moreover, EVO treatment ameliorated the oxidative stress and decreased the serum levels of pro-inflammatory cytokines in T2DM model rats. Serum untargeted metabolomics analysis indicated that the EVO treatment affected the levels of 26 metabolites, such as methionine, citric acid, cholesterol, taurocholic acid, pilocarpine, adrenic acid, and other metabolites. These metabolites were mainly related to the amino sugar and nucleotide sugar metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, and tryptophan metabolism pathways. In conclusion, EVO can reduce blood glucose and improve oxidative stress and inflammatory response in T2DM rats. These functions are related to the regulation of amino sugar and nucleotide sugar metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, and tryptophan metabolism pathways.