Tissue-resident memory T cells (T_RM) are noncirculating immune cells that contribute to the first line of local defense against reinfections. Their location at hotspots of pathogen encounter frequently exposes T_RM to tissue damage. This history of danger-signal exposure is an important aspect of T_RM-mediated immunity that has been overlooked so far. RNA profiling revealed that T_RM from liver and small intestine express P2RX7, a damage/danger-associated molecular pattern (DAMP) receptor that is triggered by extracellular nucleotides (ATP, NAD⁺). We confirmed that P2RX7 protein was expressed in CD8⁺ T_RM but not in circulating T cells (T_CIRC) across different infection models. Tissue damage induced during routine isolation of liver lymphocytes led to P2RX7 activation and resulted in selective cell death of T_RM. P2RX7 activation in vivo by exogenous NAD⁺ led to a specific depletion of T_RM while retaining T_CIRC. The effect was absent in P2RX7-deficient mice and after P2RX7 blockade. TCR triggering down-regulated P2RX7 expression and made T_RM resistant to NAD-induced cell death. Physiological triggering of P2RX7 by sterile tissue damage during acetaminophen-induced liver injury led to a loss of previously acquired pathogen-specific local T_RM in wild-type but not in P2RX7 KO T cells. Our results highlight P2RX7-mediated signaling as a critical pathway for the regulation of T_RM maintenance. Extracellular nucleotides released during infection and tissue damage could deplete T_RM locally and free niches for new and infection-relevant specificities. This suggests that the recognition of tissue damage promotes persistence of antigen-specific over bystander T_RM in the tissue niche.