Deregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes, including Huntington's disease (HD). DREAM/calsenilin/KChIP-3 is a multifunctional Ca2+ binding protein that controls the expression level and/or the activity of several proteins related to Ca2+ homeostasis, neuronal excitability and neuronal survival. We found that expression of endogenous DREAM (DRE antagonist modulator) is reduced in the striatum of R6 mice, in STHdh-Q111/111 knock in striatal neurons and in HD patients. DREAM down regulation in R6 striatum occurs early after birth, well before the onset of motor coordination impairment, and could be part of an endogenous mechanism of neuroprotection, since i) R6/2 mice hemizygous for the DREAM gene (R6/2xDREAM+/-) showed delayed onset of locomotor impairment and prolonged lifespan, ii) motor impairment after chronic administration of 3-NPA was reduced in DREAM knockout mice and enhanced in daDREAM transgenic mice and, iii) lentiviral-mediated DREAM expression in STHdh-Q111/111 knock in cells sensitizes them to oxidative stress. Transcriptomic analysis showed that changes in gene expression in R6/2 striatum were notably reduced in R6/2xDREAM+/- striatum. Chronic administration of repaglinide, a molecule able to bind to DREAM in vitro and to accelerate its clearance in vivo, delayed the onset of motor dysfunction, reduced striatal loss and prolonged the lifespan in R6/2 mice. Furthermore, exposure to repaglinide protected STHdh-Q111/111 knock in striatal neurons sensitized to oxidative stress by lentiviral-mediated DREAM overexpression. Thus, genetic and pharmacological evidences disclose a role for DREAM silencing in early neuroprotective mechanisms in HD.