Background Heterozygous familial hypercholesterolemia (FH) is a common genetic disorder causing premature cardiovascular disease. Despite this, there is no national screening program in the United States to identify individuals with FH or likely pathogenic FH genetic variants. Methods and Results The clinical characteristics and FH variant status of 49 738 UK Biobank participants were used to develop a regression model to predict the probability of having any FH variants. The regression model and modified Dutch Lipid Clinic Network criteria were applied to 39 790 adult participants (aged ≥20 years) in the National Health and Nutrition Examination Survey to estimate the yield of FH screening programs using Dutch Lipid Clinic Network clinical criteria alone (excluding genetic variant status), genetic testing alone, or combining clinical criteria with genetic testing. The regression model accurately predicted FH variant status in UK Biobank participants (observed prevalence, 0.27%; predicted, 0.26%; area under the receiver‐operator characteristic curve, 0.88). In the National Health and Nutrition Examination Survey, the estimated yield per 1000 individuals screened (95% CI) was 3.7 (3.0–4.6) FH cases with the Dutch Lipid Clinic Network clinical criteria alone, 3.8 (2.7–5.1) cases with genetic testing alone, and 6.6 (5.3–8.0) cases by combining clinical criteria with genetic testing. In young adults aged 20 to 39 years, using clinical criteria alone was estimated to yield 1.3 (95% CI, 0.6–2.5) FH cases per 1000 individuals screened, which was estimated to increase to 4.2 (95% CI, 2.6–6.4) FH cases when combining clinical criteria with genetic testing. Conclusions Screening for FH using a combination of clinical criteria with genetic testing may increase identification and the opportunity for early treatment of individuals with FH.