As prenatal methamphetamine (MA) exposure results in long-term hippocampus-dependent cognitive deficits, the increased MA use in women of childbearing age is of great concern. As mice are most commonly used in genetic models, we started to study the potential effects of neonatal MA exposure in female and male mice on brain function 3 months later. As histamine (HA) might mediate some effects of MA in adulthood, we also tested whether in neonates HA might mediate the long-term effects of MA using HA H(3) receptor agonists and antagonists. Stimulation of HA H(3) receptors by H(3) agonists inhibits HA synthesis and release, whereas inhibition of H(3) receptors by H(3) receptor antagonists increases HA release. MA (5 mg/kg), the H(3) receptor antagonist thioperamide (5 mg/kg), and the H(3) receptor agonist immepip (5 mg/kg) alone or in the presence of MA (5 mg/kg) were administered once daily from postnatal days 11 to 20 and the mice were tested at 3 months of age. Here we show that in mice exposure to MA early in life causes sex-dependent impairments in object recognition, spatial learning, and memory in the water maze, and pre-pulse inhibition in adulthood. HA mediates these impairments. Increasing HA release mimicked, whereas inhibiting HA release blocked the long-term detrimental MA effects. This model could be used to determine the role of genetic and environmental factors in MA-dependent cognitive impairments and to develop therapeutic strategies to inhibit them.