After an infection, pathogen-specific tissue-resident memory T cells (T_RM cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create T_RM cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how T_RM cells provide such pathogen protection. Here, we demonstrate that activated T_RM cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This “pathogen alert” allows skin T_RM cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8⁺ T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants.