One mechanism of action of thyroid disrupting compounds is the competition for thyroid hormone (TH) binding sites on vertebrate serum transport proteins, including transthyretin (TTR) and albumin (ALB). An in vitro competitive binding assay was optimized for use with thyroxine (T4) and human TTR or ALB. This assay was applied for two classes of novel and environmentally relevant flame retardant (FR) chemicals, and/or some degradation products; organophosphate (OP) triesters, and tetradecabromo-1,4-diphenoxybenzene (TeDB-DiPhOBz). Structure-related differences in the binding of these ligands with TTR or ALB were observed, including a newly discovered apparent allosteric interaction of OP esters with TTR that enhances binding of T4. Degradation products of TeDB-DiPhOBz are ligands for human TTR and ALB in vitro, as well as gull TTR in silico, with para-hydroxylated lower brominated congeners being the strongest binders. Overall, results indicate potential interference of these novel FR contaminants with human TH transport, in a structure-dependent manner.