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Background The National Institutes of Health (NIH) mobilized more than $4 billion in extramural funding for the COVID-19 pandemic. Assessing the research output from this effort is crucial to understanding how the scientific community leveraged federal funding and responded to this public health crisis. Methods NIH-funded COVID-19 grants awarded between January 2020 and December 2021 were identified from NIH Research Portfolio Online Reporting Tools Expenditures and Results using the "COVID-19 Response" filter. PubMed identifications of publications under these grants were collected and the NIH iCite tool was used to determine citation counts and focus (eg, clinical, animal). iCite and the NIH's LitCOVID database were used to identify publications directly related to COVID-19. Publication titles and Medical Subject Heading terms were used as inputs to a machine learning–based model built to identify common topics/themes within the publications. Results and Conclusions We evaluated 2401 grants that resulted in 14 654 publications. The majority of these papers were published in peer-reviewed journals, though 483 were published to preprint servers. In total, 2764 (19%) papers were directly related to COVID-19 and generated 252 029 citations. These papers were mostly clinically focused (62%), followed by cell/molecular (32%), and animal focused (6%). Roughly 60% of preprint publications were cell/molecular-focused, compared with 26% of nonpreprint publications. The machine learning–based model identified the top 3 research topics to be clinical trials and outcomes research (8.5% of papers), coronavirus-related heart and lung damage (7.3%), and COVID-19 transmission/epidemiology (7.2%). This study provides key insights regarding how researchers leveraged federal funding to study the COVID-19 pandemic during its initial phase. [ABSTRACT FROM AUTHOR]