Parkinson's disease (PD) is the most common neurodegenerative movement disorder and imposes a severe social and economic burden on ageing populations. PD results from the progressive loss of dopaminergic neurons that is accompanied by a chronic neuroinflammatory response that propagates disease progression. However, the precise mechanisms and inflammatory mediators that sustain chronic neuroinflammation in PD remain to be elucidated. In this study, we demonstrate widespread upregulation of complement proteins in PD patients, and in four distinct animal models of PD. Genetic deletion of key complement effectors highlighted a critical role for complement C5a receptors (C5aR1) in driving neurodegeneration in response to dopaminergic toxins. Fibrillar α-synuclein aggregates, the predominant protein found in PD brain Lewy bodies, directly activated complement to generate C5a and increased C5aR1 expression in microglia. Oral administration of a brain-permeable C5aR1 antagonist significantly protected against behavioral motor deficits, microglial activation, and nigrostriatal dopaminergic degeneration in two preclinical PD models. Notably, delaying drug administration until symptom onset remained neuroprotective. Mechanistically, microglial NLRP3 inflammasome activation was impaired in the absence of C5aR1 signaling. Indeed, both mouse and human microglia were unable to secrete IL-1b in response to α-synuclein in the presence of C5aR1 inhibitors. Taken together, our results suggest that complement activation and persistent C5a generation by mis-folded protein aggregates in the PD brain can contribute to microglial NLRP3 inflammasome activation, and thereby exacerbate disease pathology. Selective targeting of C5aR1 may therefore be a viable therapeutic strategy to reduce microglial inflammation, and thus slow disease progression in PD.