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Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied microglial activation by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NLRP3 inflammasome via Toll-like receptor-2 and -5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn, but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation which can be prevented by NLRP3 inhibition.