Previous studies indicated that North American wild rice (WIR) reduced atherosclerosis and vascular inflammation in low-density lipoprotein receptor knockout mice. The effects of WIR on hyperglycemia in diabetic animal models have not been documented. The present study aims to determine the impact of WIR on glucose metabolism in high-fat (HF)-induced diabetic mice and a key modulator. Male C57 BL/J6 mice were treated with a control diet and a HF diet supplemented with 26% (weight/weight, a substitute for carbohydrates in the diet) of WIR or white rice (WHR) (n = 8/group) for 11 weeks. HF + WHR diet significantly increased fasting plasma glucose, cholesterol, triglycerides, insulin, insulin resistance, monocyte adhesion, and the levels of relevant inflammatory mediators (tumor necrotic factor-α, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1) in mice compared to the control diet (p < 0.01). HF + WIR significantly reduced HF diet-induced metabolic and inflammatory changes compared to the HF + WHR diet (p < 0.01). Metabolomics analysis indicated that an array of metabolites related to glucose metabolism was significantly more abundant in WIR than in WHR, including adenosine 5′-monophosphate (AMP), a potent agonist for AMP-activated protein kinase or AMPK. WIR normalized HF diet-induced reduction in the abundance of phospho-AMPKα in skeletal muscle, liver, and adipose tissue from the mice. The findings for the first time demonstrated that WIR decreased HF diet-induced hyperglycemia in mice compared to WHR. The metabolic benefits of WIR may result, at least in part, from the activation of AMPKα in insulin-sensitive tissue in the mice.