Objective To study the effects and mechanism of olanzapine on energy consumption and glucose metabolism in male mice. Methods Ten C57BL/6J male mice were randomly divided into two groups. The mice in two groups were given olanzapine or its solvent by gavage separately for 2 weeks. Food intake, body weight, fasting blood glucose, glucose tolerance and insulin tolerance were recorded. Energy consumption of 24 h was monitored. And expressions of hepatic glucose metabolism related genes were compared. Results After administration of olanzapine for two weeks, insulin resistance and hyperglycemia were observed, oxygen and energy consumptions were significantly decreased during the daytime, and respiratory exchange ratio showed a downward trend which indicated that the oxidized substrates were transferred from glucose to fat. And mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-pase) were significantly increased. Conclusions Olanzapine-induced hyperglycemia may not dependent on hyperphagia and weight gain. Olanzapine can directly induce insulin resistance and promote hepatic gluconeogenesis.