Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by motor as well as nonmotor symptoms for which there is currently no cure. The Q175 mouse model of HD recapitulates many of the symptoms identified in HD patients including disruptions of the sleep/wake cycle. In this study, we sought to determine if the daily administration of the histamine-3 receptor (H3R) antagonist/inverse agonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) would improve nonmotor symptoms in the Q175 line. This class of drugs acts on autoreceptors found at histaminergic synapses and results in increased levels of histamine (HA). HA is a neuromodulator whose levels vary with a daily rhythm with peak release during the active cycle and relatively lower levels during sleep. H3Rs are widely expressed in brain regions involved in cognitive processes and activation of these receptors promotes wakefulness. We administered GSK189254 nightly to homozygote and heterozygote Q175 mice for 4 weeks and confirmed that the plasma levels of the drug were elevated to a therapeutic range. We demonstrate that daily treatment with GSK189254 improved several behavioral measures in the Q175 mice including strengthening activity rhythms, cognitive performance and mood as measured by the tail suspension test. The treatment also reduced inappropriate activity during the normal sleep time. The drug treatment did not alter motor performance and coordination as measured by the challenging beam test. Our findings suggest that drugs targeting the H3R system may show benefits as cognitive enhancers in the management of HD.