Congenital heart disease (CHD) is a leading cause of pediatric morbidity and mortality worldwide. The genetics of CHD in African populations is not well understood, although it has been shown in other settings that a genetic diagnosis can have implications for patient management and risk stratification. In this study, we aimed to identify pathogenic and likely pathogenic (P/LP) variants in a cohort of patients with CHD from Southern Africa. Exome sequencing was used to screen 356 patients with diverse cardiac phenotypes from South Africa and Namibia. A P/LP variant was identified in 28 patients (7.9%). Analysis of 11 parent-child trios revealed a further LP variant in MYLK in 1 patient, bringing the overall yield to 8.1%. Variants of uncertain significance with high pathogenic potential were found in 30 additional patients. NOTCH1, MYH11, and MYH6 had the most recurrent variants in this cohort. Our data expand on the phenotypic spectrum of many established CHD genes, including the overlap between syndromic CHD genes and nonsyndromic presentation, and a potential link between aortopathy genes and conotruncal anomalies such as Tetralogy of Fallot. Variants were identified across the spectrum of CHD subtypes, with an increased yield in patients with atrioventricular septal defects and syndromic CHD, and a slight enrichment of P/LP variants in patients who died after CHD surgery. There were significantly fewer P/LP variants in patients who were of mixed ancestry. Together, these data confirm a role for rare deleterious variation in nonsyndromic CHD and demonstrate that a P/LP variant can be identified in 8% of patients from Southern Africa.