Weight gain and its related metabolic disorders are major side-effects associated with second generation antipsychotic drug (SGA) treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor (H1R) contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16 and 36 days) on DVC AMPK signaling in olanzapine-induced weight gain, and whether these changes are associated with olanzapine-induced H1 receptor antagonism. During the 8-day olanzapine treatment the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK: activated AMPK) as well as its directly downstream phospho-Acetyl-CoA carboxylase (pACC) was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36-day olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1R protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1R level after the 8, 16, and 36-day olanzapine treatments. Moreover, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine-induced DVC AMPK activation may be at least partially related to olanzapine's antagonistic effect on the H1R.