Previous studies have shown that the ATP-P2X4 receptor signaling pathway mediates the activation of the Nod-like receptor family protein3 (NLRP3) inflammasome. The NLRP3 inflammasome may promote renal interstitial inflammation in diabetic nephropathy. As inflammation also plays an important role in the pathogenesis of Parkinson\'s disease, we hypothesized that the ATP-P2X4 receptor signaling pathway may activate the NLRP3 inflammasome in Parkinson\'s disease. A male rat model of Parkinson\'s disease was induced by stereotactic injection of 6-hydroxydopamine into the pars compacta of the substantia nigra. The P2X4 receptor and the NLRP3 inflammasome (interleukin-1β and interleukin-18) were activated. Intracerebroventricular injection of the selective P2X4 receptor antagonist 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) or knockdown of P2X4 receptor expression by siRNA inhibited the activation of the NLRP3 inflammasome and alleviated dopaminergic neurodegeneration and neuroinflammation. Our results suggest that the ATP-P2X4 receptor signaling pathway mediates NLRP3 inflammasome activation, dopaminergic neurodegeneration, and dopamine levels. These findings reveal a novel role of the ATP-P2X4 axis in the molecular mechanisms underlying Parkinson\'s disease, thus providing a new target for treatment. This study was approved by the Animal Ethics Committee of Qingdao University, China, on March 5, 2015 (approval No. QYFYWZLL 26119).