Background: Cognitive impairment is frequent in Parkinson’s disease (PD) and several neurotransmitter changes have been reported since the time of diagnosis, although seldom investigated altogether in the same patient cohort. Objective: Our aim was to evaluate the association between neurotransmitter impairment, brain metabolism, and cognition in a cohort of de novo, drug-naïve PD patients. Methods: We retrospectively selected 95 consecutive drug-naïve PD patients (mean age 71.89±7.53) undergoing at the time of diagnosis a brain [18F]FDG-PET as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123I]FP-CIT-SPECT as a marker and dopaminergic deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological battery. Results: Positive correlations were observed between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic tone and working memory (r = 0.304, p = 0.003), (iii) qEEG slowing in the posterior leads and both memory (r = 0.299, p = 0.004) and visuo-spatial functions (r = 0.357, p < 0.001). Conclusions: In subjects with PD, the impact of regional metabolism and diffuse projection systems degeneration differs across cognitive domains. These findings suggest possible tailored approaches to the treatment of cognitive deficits in PD.