Atopic dermatitis (AD) is a common illness that has been associated with filaggrin gene (FLG) loss of function (LoF) variation. In African Americans, a group that commonly has AD and has not been well studied, FLG LoF variation is rarely found. Our objective was to use massively parallel sequencing to evaluate FLG LoF variation in children of African ancestry to evaluate the association between FLG LoF variation and AD and AD persistence. We studied 262 African American children with AD. Nine unique FLG exon 3 LoF variants were identified for an overall minor variant frequency of 6.30% (95% confidence interval [CI] = 4.37–8.73). The most common variants were p.R501X (1.72%, 95% CI = 0.79–3.24), p.S3316X (1.34%, 95% CI = 0.54–2.73), and p.R826X (0.95%, 95% CI = 0.31–2.2). Over an average follow-up period of 96.4 (95% CI = 92.0–100.8) months, African American children with FLG LoF were less likely to be symptom free (odds ratio = 0.36, 95% CI = 0.14–0.89, P = 0.027) compared with a FLG wild-type child. In contrast to previous reports, uncommon FLG LoF variants in African American children exist and are associated with AD and more persistent AD. In contrast to Europeans, no FLG LoF variants predominate in African American children. Properly determining FLG LoF status requires advanced sequencing techniques.