Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a glycosylated type I transmembrane protein that forms soluble GPNMB upon maturation. This study aimed to explore the relationship between plasma GPNMB levels in patients with Parkinson's disease (PD) and their clinical manifestations, as well as their correlations with specific brain regions identified through imaging analysis. This study included patients with PD and healthy control subjects whose plasma GPNMB levels measured by enzyme-linked immunosorbent assay (ELISA). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) scale. The imaging analysis employed voxel-based morphometry (VBM) to detect changes in gray matter volume, with the left lentiform nucleus identified as the region of interest (ROI). The results showed that plasma GPNMB levels were significantly correlated with PD-related cognitive impairment. Specifically, elevated plasma GPNMB levels were associated with deficits in scores for MoCA subitems related to delayed memory. The imaging analysis revealed a moderate negative correlation between plasma GPNMB levels and the gray matter volume in the left putamen, suggesting that this area may be a potential site of action for GPNMB in the pathology of PD. This study is the first comprehensive investigation into the interrelationships between plasma GPNMB levels and the clinical symptoms and imaging characteristics of PD.