Hydroponic vegetable production is increasing globally, but there is a lack of science-based recommendations to ensure their food safety. Specifically, there is limited evidence for establishing water management strategies. The purpose of this study was to determine the survival of Salmonella Typhimurium and Listeria monocytogenes in commercial nutrient flow technology (NFT) systems during the lifecycle of lettuce exposed to sporadic or extreme contamination. NFT systems were inoculated with Salmonella Typhimurium or Listeria monocytogenes, and nutrient solution, rockwool, roots, and lettuce leaves were collected over the lettuce production cycle for pathogen enumeration and detection. Both human pathogens persisted in the lettuce NFT growing system throughout the growth cycle of lettuce. Salmonella Typhimurium and L. monocytogenes accumulated in rockwool medium and on lettuce roots and were transferred to the leaves at quantifiable levels from the contaminated nutrient solution. In the nutrient solution, Salmonella concentration under sporadic and extreme conditions declined significantly 24 h after inoculation and again 7 days post-inoculation (p < 0.0001). Under extreme conditions, the concentration did not change significantly after 7 days, while under sporadic conditions, the concentration declined again 14 days post-inoculation in the nutrient solution collected from the reservoirs. L. monocytogenes populations in the nutrient solution fluctuated significantly over the 28-day growth cycle (p < 0.0001). Under extreme conditions, L. monocytogenes concentrations in the nutrient solution declined, while under sporadic conditions, the populations increased. The findings of this study, for the first time, describe human pathogen survival in commerical NFT systems and highlight the urgent need for novel approaches to mitigating the risks from nutrient solution contaminaiton in hydroponics.