Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the beneficial effects of a PARP-1 inhibitor in HD. In this study, we investigated the neuroprotective effect of Olaparib, an inhibitor of PARP-1, in the mouse model of Huntington’s disease. R6/2 mice were administered Olaparib or vehicle from pre-symptomatic to late stages. Behavioral studies were performed to investigate clinical effects of the compound. Immunohistochemical and Western blotting studies were performed to evaluate neuroprotection and the impact of the compound on the pathway of neuronal death in the HD mice. Our results indicate that Olaparib administration starting from the pre-symptomatic stage of the neurodegenerative disease increased survival, ameliorated the neurological deficits, and improved clinical outcomes in neurobehavioral tests mainly by modulating the inflammasome activation. These results suggest that Olaparib, a commercially available drug already in use as an anti-neoplastic compound, exerts a neuroprotective effect and could be a useful pharmaceutical agent for Huntington’s disease therapy.