Objective COVID-19 poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers. Methods The Clinical and Translational Science Award (CTSA) Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We developed solutions to extract, aggregate, and harmonize data across organizations and data models, and created a secure data enclave to enable efficient, transparent, and reproducible collaborative analytics. Organized in inclusive workstreams, in two months we created: legal agreements and governance for organizations and researchers; data extraction scripts to identify and ingest positive, negative, and possible COVID-19 cases; a data quality assurance and harmonization pipeline to create a single harmonized dataset; population of the secure data enclave with data, machine learning, and statistical analytics tools; dissemination mechanisms; and a synthetic data pilot to democratize data access. Discussion The N3C has demonstrated that a multi-site collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multi-organizational clinical data for COVID-19 analytics. We expect this effort to save lives by enabling rapid collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care and thereby reduce the immediate and long-term impacts of COVID-19. LAY SUMMARY COVID-19 poses societal challenges that require expeditious data and knowledge sharing. Though medical records are abundant, they are largely inaccessible to outside researchers. Statistical, machine learning, and causal research are most successful with large datasets beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many clinical centers to reveal patterns in COVID-19 patients. To create N3C, the community had to overcome technical, regulatory, policy, and governance barriers to sharing patient-level clinical data. In less than 2 months, we developed solutions to acquire and harmonize data across organizations and created a secure data environment to enable transparent and reproducible collaborative research. We expect the N3C to help save lives by enabling collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care needs and thereby reduce the immediate and long-term impacts of COVID-19.