When Hurricane Harvey landed along the Texas coast on August 25, 2017, it caused massive flooding and damage and displaced tens of thousands of residents of Harris County, Texas. Between August 29 and September 23, Harris County, along with community partners, operated a megashelter at NRG Center, which housed 3365 residents at its peak. Harris County Public Health conducted comprehensive public health surveillance and response at NRG, which comprised disease identification through daily medical record reviews, nightly “cot-to-cot” resident health surveys, and epidemiological consultations; messaging and communications; and implementation of control measures including stringent isolation and hygiene practices, vaccinations, and treatment. Despite the lengthy operation at the densely populated shelter, an early seasonal influenza A (H3) outbreak of 20 cases was quickly identified and confined. Influenza outbreaks in large evacuation shelters after a disaster pose a significant threat to populations already experiencing severe stressors. A holistic surveillance and response model, which consists of coordinated partnerships with onsite agencies, in-time epidemiological consultations, predesigned survey tools, trained staff, enhanced isolation and hygiene practices, and sufficient vaccines, is essential for effective disease identification and control. The lessons learned and successes achieved from this outbreak may serve for future disaster response settings. (Disaster Med Public Health Preparedness. 2019;13:97-101)