Abstract Brominated phenolic compounds (BPCs) are found in the environment, and in human and wildlife tissues, and some are considered to have endocrine disrupting activities. The goal of this study was to determine how structural differences of 3 BPC classes impact binding affinities for the thyroid receptor beta (TRβ) in humans and zebrafish. BPC classes included halogenated bisphenol A derivatives, halogenated oxidative transformation products of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), and brominated phenols. Affinities were assessed using recombinant TRβ protein in competitive binding assays with 125I-triiodothyronine (125I-T3) as the radioligand. Zebrafish and human TRβ displayed similar binding affinities for T3 (Ki = 0.40 and 0.49 nM) and thyroxine (T4, Ki = 6.7 and 6.8 nM). TRβ affinity increased with increasing halogen mass and atomic radius for both species, with the iodinated compounds having the highest affinity within their compound classes. Increasing halogen mass and radius increases the molecular weight, volume, and hydrophobicity of a compound, which are all highly correlated with increasing affinity. TRβ affinity also increased with the degree of halogenation for both species. Human TRβ displayed higher binding affinities for the halogenate bisphenol A compounds, whereas zebrafish TRβ displayed higher affinities for 2,4,6-trichlorophenol and 2,4,6-trifluorophenol. Observed species differences may be related to amino acid differences within the ligand binding domains. Overall, structural variations impact TRβ affinities in a similar manner, supporting the use of zebrafish as a model for TRβ disruption. Further studies are necessary to investigate how the identified structural modifications impact downstream receptor activities and potential in vivo effects.