In the early stages of Huntington’s disease (HD) there is an excess of dopamine production and an over-activation of dopamine D1 receptors (D1R) that can produce not only an imbalance in dopaminergic neurotransmission but can also directly lead to signalling cascades that induce cell death. However, simply blocking of D1R has important drawbacks as it disrupts several physiological functions. Importantly, many of these G-protein coupled receptors (GPCRs) may interact and form the so called heteromers. These receptor complexes confer novel functions and have been proposed as excellent candidates to modulate receptor signalling. Here we propose a new and provocative strategy to reduce the D1R over-activation effects in HD by targeting the recently described receptor complexes of D1R and the histamine receptors H3 (H3R). We show the expression of D1R-H3R heteromers in a HD model of striatal neuronal progenitor cells and in different brain areas of mouse models of HD in the early but not in the late stages of the disease as well as in human control subjects and in grade 2 HD patients but not in grade 3 or 4 HD patients. Upon co-activation of D1R-H3R heteromers, H3R ligands act as a “molecular brake” for D1R signalling. D1R-induced cell death in cells and in brain slices and the signalling cascades responsible for this death are reduced by H3R ligands targeting D1R-H3R heteromers. Chronic treatment of pre-symptomatic HD mice with an H3R antagonist can restore both motor learning and spatial and recognition memory deficits of these animals and inhibits the loss of heteromer expression at more advanced diseases stages. Overall, these results demonstrate that D1R-H3R heteromers play a pivotal role in controlling dopaminergic neurotransmission and indicate that D1R-H3R heteromers can be a new target for treating HD in the pre-symptomatic stages of the disease.