Ergothioneine (EGT), an active compound in many edible mushrooms, has considerable potential for therapeutic intervention in neurodegenerative diseases. However, whether EGT can safely alleviate symptoms of Parkinson’s disease (PD) and its neurophysiological mechanisms remain unclear. In this study, 6-hydroxydopamine (6-OHDA) mouse model of PD was chosen to mimic the pathological progression observed in the early stages of PD patients. After 4 weeks of EGT treatment (8 mg/(kg·day)), there was a significant improvement in motor impairments of 6-OHDA mice with a reduction in dopaminergic neuronal loss in the substantia nigra pars compacta. Using in vivo multi-electrophysiological recordings, we found that EGT treatment increased the firing rates of neurons in the primary motor cortex (M1) of 6-OHDA mice. In addition, EGT treatment notably reduced pathological β oscillations (13–30 Hz) and β-γ phase-amplitude coupling (β-γ PAC) in both the M1 and the subthalamic nucleus of 6-OHDA mice. These physiological recoveries after EGT treatment were accompanied by increased spine density of pyramidal neurons and upregulated expression of glutamate receptors in the M1. Our findings suggest that EGT is a promising natural neuroprotective agent for slowing or preventing PD progression.