In 2011, the US Secretary of Health and Human Services recommended universal screening of newborns for critical congenital heart defects (CCHDs), yet few estimates of the number of infants with CCHDs likely to be detected through universal screening exist. Our objective was to estimate the number of infants with nonsyndromic CCHDs in the United States likely to be detected (true positives) and missed (false negatives) through universal newborn CCHD screening. We developed a simulation model based on estimates of birth prevalence, prenatal diagnosis, late detection, and sensitivity of newborn CCHD screening through pulse oximetry to estimate the number of true-positive and false-negative nonsyndromic cases of the 7 primary and 5 secondary CCHD screening targets identified through screening. We estimated that 875 (95% uncertainty interval UI: 705-1060) US infants with nonsyndromic CCHDs, including 470 (95% UI: 360-585) infants with primary CCHD screening targets, will be detected annually through newborn CCHD screening. An additional 880 (UI: 700-1080) false-negative screenings, including 280 (95% UI: 195-385) among primary screening targets, are expected. We estimated that similar numbers of CCHDs would be detected under scenarios comparing "lower" (∼19%) and "higher" (∼41%) than current prenatal detection prevalences. A substantial number of nonsyndromic CCHD cases are likely to be detected through universal CCHD screening; however, an equal number of false-negative screenings, primarily among secondary targets of screening, are likely to occur. Future efforts should document the true impact of CCHD screening in practice.