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. Using publically available proteomic data we identified widespread dysregulation of the innate immune complement cascade in PD patients. We also demonstrate complement upregulation in multiple distinct animal models of PD. Genetic deletion of key complement effectors in PD mice 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. To test the therapeutic potential of targeting complement in PD, we utilised a cyclic hexapeptide antagonist of C5aR1 which was administered orally to PD mice. Treatment significantly protected against behavioral motor deficits and nigrostriatal dopaminergic degeneration in two preclinical PD models. Notably, delaying drug administration until symptom onset remained neuroprotective. Live visualisation of neuroinflammation using [¹⁸F]DPA-714 PET/CT-imaging also demonstrated that both prophylactic and therapeutic inhibition of C5aR1 blunted microglial activation in living mice. Mechanistically, α-synuclein driven inflammasome activation in human and mouse microglia was impaired in the absence of C5aR1 signaling. Targeting this complement-microglia-inflammasome axis with cyclic peptide complement inhibitors presents a promising therapeutic approach to mitigate neuroinflammation and slow neuronal death in people living with PD.