Olanzapine, a popular atypical antipsychotic, has unexpected and unexplained side effects leading to obesity and diabetes. It causes obesity, glucose intolerance and surprisingly decreases FFA. We characterized acute metabolic effects in rodents and sought to translate these findings to humans (double blind, crossover trial). Olanzapine rapidly caused glucose intolerance in rodents and elevated whole-body lipid utilization, evident by accelerated losses of plasma triglycerides and decreased FFA after food deprivation, lipid challenge or both, elevated tissue FFA uptake (~2-fold), rises in long-chain 3-hydroxylated acyl-carnitines, and RER suppression. In skeletal muscle this was associated with a ~50% decrease of malonyl-CoA and parallel losses of anapleurotic metabolites and TCA cycle precursors of malonyl-CoA, rather than AMPK activation or ACC1/2 inhibition. Screening other antipsychotics revealed that ability to decrease RER correlated with severity of clinical side effects. Similarly, olanzapine (3 day) acutely decreased FFA and impaired glucose tolerance in healthy volunteers. Unlike rodents, however, olanzapine increased plasma triglycerides. Collectively, atypical antipsychotics have metabolic effects within the first days of treatment. Data suggests excessive fat oxidation is associated with the development of glucose intolerance in humans and rodents (1R01DK084428).