BackgroundParkinson’s disease (PD) is characterized by a progressive degeneration of dopaminergic neurons, which leads to irreversible loss of peripheral motor functions. Death of dopaminergic neurons induces an inflammatory response in microglial cells, which further exacerbates neuronal loss. Reducing inflammation is expected to ameliorate neuronal loss and arrest motor dysfunctions. Because of the contribution of the NLRP3 inflammasome to the inflammatory response in PD, we targeted NLRP3 using the specific inhibitor OLT1177®.MethodsWe evaluated the effectiveness of OLT1177®in reducing the inflammatory response in an MPTP neurotoxic model of PD. Using a combination of in vitro and in vivo studies, we analyzed the effects of NLRP3 inhibition on pro-inflammatory markers in the brain, α-synuclein aggregation, and dopaminergic neuron survival. We also determined the effects of OLT1177®on locomotor deficits associated with MPTP and brain penetrance.ResultsTreatment with OLT1177®prevented the loss of motor function, reduced the levels of α-synuclein, modulated pro-inflammatory markers in the nigrostriatal areas of the brain, and protected dopaminergic neurons from degeneration in the MPTP model of PD. We also demonstrated that OLT1177®crosses the blood–brain barrier and reaches therapeutic concentrations in the brain.ConclusionsThese data suggest that targeting the NLRP3 inflammasome by OLT1177®may be a safe and novel therapeutic approach to arrest neuroinflammation and protect against neurological deficits of Parkinson’s disease in humans.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12974-023-02830-w.