As the USA and the rest of the world raced to fight the COVID-19 pandemic, years of investments from the National Center for Advancing Translational Sciences allowed for informatics services and resources at CTSA hubs to play a significant role in addressing the crisis. CTSA hubs partnered with local and regional partners to collect data on the pandemic, provide access to relevant patient data, and produce data dashboards to support decision-making. Coordinated efforts, like the National COVID Cohort Collaborative (N3C), helped to aggregate and harmonize clinical data nationwide. Even with significant informatics investments, some CTSA hubs felt unprepared in their ability to respond to the fast-moving public health crisis. Many hubs were forced to quickly evolve to meet local needs. Informatics teams expanded critical support at their institutions which included an engagement platform for clinical research, COVID-19 awareness and education activities in the community, and COVID-19 data dashboards. Continued investments in informatics resources will aid in ensuring that tools, resources, practices, and policies are aligned to meet local and national public health needs.