Extracellular purines not only play a critical role in maintaining a balanced inflammatory response but may also trigger disproportionate inflammation in various kidney pathologies. Extracellular ATP is the most well-characterized inflammatory purine, which serves as a potent extracellular danger-associated molecular pattern. It signals through the P2 purinoreceptors during both acute and chronic kidney damage. The purinoreceptor P2X7 (P2X7R) has been extensively studied in kidney disease because of its potent ability to enhance inflammation by activating the nucleotide-binding oligomerization domain, leucine rich repeat family pyrin domain containing 3 inflammasome in both immune and parenchymal tubular cells and potential role in immunometabolic reprogramming. We will explore how, following a primary insult to the kidney, disturbance of purinergic balance characterized by extracellular ATP-mediated P2X7R activation exacerbates AKI. Second, we will describe how persistent purinergic disbalance promotes a P2X7R-mediated protracted inflammatory reaction leading to the progression of CKD of different etiologies. Finally, we will also highlight the relevant and emerging role of P2X7R signaling in both antigen-presenting cells and adaptive immune cells to modulate cellular and humoral immune responses in kidney transplantation and hypertension. This review underscores that ATP-P2X7R axis is a key driver of pathologic purinergic signaling, representing a largely unexplored but highly promising clinical target against a wide spectrum of kidney diseases.