There is increasing interest in developing therapeutic interventions aimed at preventing neuroinflammation in Parkinson's disease (PD). However, the specific characteristics of inflammation across different cell types and the underlying mechanisms of PD-related inflammation remain inadequately understood. In this study, we conducted an analysis of single-cell RNA sequencing (scRNA-seq) and microarray data derived from human PD midbrain tissue, specifically focusing on the substantia nigra compacta (SNc). These datasets were sourced from the (GEO) database. We utilized GSVA, GSEA, as well as KEGG and GO analyses to explore transcriptional variations associated with PD. Furthermore, trajectory and SCENIC analyses were conducted to uncover the mechanisms underlying PD progression. Subsequent animal and cellular experiments validated the role of the regulon in regulating neuroinflammation. Results: Our analysis revealed that microglia displayed the highest levels of inflammatory activity, characterized by an increased abundance of microglia in the proinflammatory activated state within the midbrain and SNc of PD patients. This finding was further validated in a PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The transcription factor STAT3 demonstrated significant upregulation and was implicated in promoting the inflammatory response and activating microglia within the PD context. In the 1-methyl-4-phenylpyridine (MPP +)-induced BV2 cell model, inhibition of STAT3 led to reduced levels of inflammation, hindered STAT3 phosphorylation, and decreased the production of inflammatory factors. Furthermore, the downregulation of P-STAT3 alleviated the harmful effects on SH-SY5Y cells that were cocultured in the conditioned medium. Conclusions: Our study underscored the pivotal role of the transcription factor STAT3 as a central regulator of proinflammatory activation in microglia within PD. These findings offer fresh insights into PD pathogenesis and suggest potential avenues for the development of novel therapeutic strategies.