To prevent viral spread cells must commit apoptosis upon initial indications of infection. However, decisions based on limited evidence can be erroneous and cause unnecessary tissue damage. How cells optimize their decision making strategy is unclear. Here we show that exposure to TNF, which is secreted by macrophages during viral infection, causes cells to change their decision strategy from “slow and accurate” to a “fast and error-prone”. Mathematical modeling combined with experiments in cell culture and mouse corneas shows that the regulation of the apoptotic decision strategy is critical to prevent HSV-1 spread. These findings demonstrate that immune regulation of cellular cognitive processes dynamically changes a tissues’ tolerance to damage, which is required to protect against pathogen spread.