Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons (DNs). The role of purinergic receptor P2X ligand-gated ion channel 7 (P2X7R) in mediating neuroinflammation and cell death in PD has attracted increasing research attention. Therefore, we conducted studies in the MPP⁺-induced PD cellular model and the MPTP-induced PD animal model to assess P2X7R regulates ferroptosis through the nuclear factor-κB (NF-κB) signaling pathway and thereby affects the PD process. This involved assessing changes in mRNA and protein levels of tyrosine hydroxylase (TH), Fe²⁺, glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and heme oxygenase 1 (HO-1) levels. Superoxide dismutase (SOD), reduced glutathione (GSH) and malondialdehyde (MDA) were detected to evaluate oxidative stress levels. Additionally, activation of NF-κB signaling pathway was determined by evaluating p65 phosphorylation levels. The study shows P2X7R suppression can increase the levels of GPX4 and FTH1 and decrease the levels of HO-1 and Fe²⁺ content, preventing the loss of DNs in the SN and ameliorating motor symptoms in PD mice. In addition, the levels of SOD and GSH increased, and the level of MDA decreased. Additionally, the silencing of P2X7R led to reduced NF-κB p65 phosphorylation, which subsequently decreased lipid peroxidation. However, phorbol 12-myristate 13-acetate (PMA), an activator of the NF-κB pathway, reversed the effect of P2X7R inhibition. These findings suggest that P2X7R activation promotes the transcription of genes associated with ferroptosis via the NF-κB pathway. This study highlights the importance of P2X7R in the regulation of ferroptosis, suggesting potential therapeutic targets for suppressing both ferroptosis and PD.