Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons (DN) in the substantia nigra and disrupted cellular maintenance. Here, we demonstrate that NDST3-mediated epigenetic reprogramming halts neuronal degeneration and restores motor function in a PD animal model. Following NDST3 administration, DN and associated circuits in the substantia nigra and striatum show marked revitalization, accompanied by significant alleviation of PD-like motor deficits. Integrative single-cell and spatial RNA sequencing with ChIP sequencing reveal that NDST3-driven reactivation of pathways linked to neuronal survival, synaptic integrity, steering compromised cells toward a resilient phenotype. By recalibrating the epigenetic landscape, NDST3 fosters cellular maintenance and functional recovery within key motor circuits. These findings highlight NDST3’s therapeutic potential as epigenetic modulator in PD. Our findings provide insights into the mechanisms underlying neuronal revitalization and underscore the promise of NDST3 as a novel agent for restoring brain function in neurodegenerative conditions.