Objectives: Using diffusion basis spectrum imaging (DBSI) to examine the microstructural changes in the substantia nigra (SN) and global white matter (WM) tracts of patients with early-stage PD.Methods: Thirty-seven age- and sex-matched patients with early-stage PD and 22 healthy controls (HCs) were enrolled in this study. All participants underwent clinical assessments and diffusion-weighted MRI scans, analyzed by diffusion tensor imaging (DTI) and DBSI to assess the pathologies of PD in SN and global WM tracts.Results: The lower DTI fraction anisotropy (FA) was seen in SN of PD patients (PD: 0.316 ± 0.034 vs HCs: 0.331 ± 0.019, p = 0.015). The putative cells marker-DBSI-restricted fraction (PD: 0.132 ± 0.051 vs HCs: 0.105 ± 0.039, p = 0.031) and the edema/extracellular space marker-DBSI non-restricted-fraction (PD: 0.150 ± 0.052 vs HCs: 0.122 ± 0.052, p = 0.020) were both significantly higher and the density of axons/dendrites marker-DBSI fiber-fraction (PD: 0.718 ± 0.073 vs HCs: 0.773 ± 0.071, p = 0.003) was significantly lower in SN of PD patients. DBSI-restricted fraction in SN was negatively correlated with HAMA scores (r = − 0.501, p = 0.005), whereas DTI-FA was not correlated with any clinical scales.In WM tracts, only higher DTI axial diffusivity (AD) among DTI metrics was found in multiple WM regions in PD, while lower DBSI fiber-fraction and higher DBSI non-restricted-fraction were detected in multiple WM regions. DBSI non-restricted-fraction in both left fornix (cres)/stria terminalis (r = −0.472, p = 0.004) and right posterior thalamic radiation (r = − 0.467, p = 0.005) was negatively correlated with MMSE scores.Conclusion: DBSI could potentially detect and quantify the extent of inflammatory cell infiltration, fiber/dendrite loss, and edema in both SN and WM tracts in patients with early-stage PD, a finding remains to be further investigated through more extensive longitudinal DBSI analysis.Clinical relevance statement: Our study shows that DBSI indexes can potentially detect early-stage PD’s pathological changes, with a notable ability to distinguish between inflammation and edema. This implies that DBSI has the potential to be an imaging biomarker for early PD diagnosis.Key Points: • Diffusion basis spectrum imaging detected higher restricted-fraction in Parkinson’s disease, potentially reflecting inflammatory cell infiltration.• Diffusion basis spectrum imaging detected higher non-restricted-fraction and lower fiber-fraction in Parkinson’s disease, indicating the presence of edema and/or dopaminergic neuronal/dendritic loss.• Diffusion basis spectrum imaging metrics correlated with non-motor symptoms, suggesting its potential diagnostic role to detect early-stage PD dysfunctions.