In this study of early functional changes in Parkinson’s disease (PD), we aimed to provide a comprehensive assessment of the development of changes in both cortical and subcortical neurophysiological brain activity, including their association with clinical measures of disease severity. Repeated resting-state MEG recordings and clinical assessments were obtained in the context of a unique longitudinal cohort study over a seven-year period using a multiple longitudinal design. We used linear mixed-models to analyze the relationship between neurophysiological (spectral power and functional connectivity) and clinical data. At baseline, early-stage (drug-naïve) PD patients demonstrated spectral slowing compared to healthy controls in both subcortical and cortical brain regions, most outspoken in the latter. Over time, spectral slowing progressed in strong association with clinical measures of disease progression (cognitive and motor). Global functional connectivity was not different between groups at baseline and hardly changed over time. Therefore, investigation of associations with clinical measures of disease progression were not deemed useful. An analysis of individual connections demonstrated differences between groups at baseline (higher frontal theta, lower parieto-occipital alpha2 band functional connectivity) and over time in PD patients (increase in frontal delta and theta band functional connectivity). Our results suggest that spectral measures are promising candidates in the search for non-invasive markers of both early-stage PD and of the ongoing disease process.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10548-023-00965-w.