Environmental factors, particularly exposure to herbicides and insecticides, are closely associated with neuroinflammation and the progression of Parkinson's disease (PD). Paraquat (PQ) is a widely used herbicide that has been reported to damage dopaminergic neurons and promote the abnormal aggregation of alpha-synuclein (ɑ-syn). We found that PQ exposure enhances the extracellular release of alpha-syn, which aggregates in dopaminergic neurons, subsequently triggering microglia activation and sustaining chronic neuroinflammation. However, the molecular mechanisms by which PQ-induced neuron-derived ɑ-syn mediates communication with microglia have not been fully elucidated. In this study, a co-culture model of mouse neuronal cells and microglia was utilized as an in vitro system. Experimental results revealed that treatment of HT-22 cells with PQ upregulated α-syn expression, causing its aggregation near the nucleus and extracellular space of neuronal cells. Furthermore, the co-culture model demonstrated that PQ-induced neuronal cells releasing endogenous ɑ-syn or cells supplemented with recombinant α-syn in vitro were capable of inducing M1 polarization of microglia. Mechanistically, α-syn was shown to bind to CD11b, a microglia-specific pattern recognition receptor, thereby inducing a sustained pro-inflammatory response and aggravate dopaminergic neuronal injury by activating NOX2 and promoting phosphorylation of its downstream signaling molecules, Src and Erk. Pharmacological inhibition of CD11b using an RGD peptide effectively effectively reduced NOX2 activation, as evidenced by decreased translocation of the NOX2 cytoplasmic subunit p47phox from the cytoplasmic to membrane, and attenuated NOX2-mediated reactive oxygen species (ROS) production and microglial activation. These finding highlight the pivotal role of CD11b in mediating microglia-driven neuroinflammatory responses. Collectively, this study provides novel insight into the underlying mechanism by which α-syn released from PQ-treated dopaminergic neurons induces neurodegeneration through activation of the CD11b-dependent Src/Erk/NOX2 pathway in microglia.