Polybrominated diphenyl ethers (PBDEs) have been shown to have a disruptive effect on the thyroid hormone system, and one possible mechanism is the direct binding of their hydroxylated metabolites (HO-PBDEs) to thyroid hormone receptors (TRs). However, the experimental data on the thyroid hormone activity of HO-PBDEs are limited, and the molecular interaction mechanism remains unclear, impeding the ecological risk assessment for these widespread contaminants. In the present research, a quantum chemical approach was developed to predict the thyroid hormone activity of HO-PBDEs using the electronic structure parameters of neutral molecules. The ab initio HF/6-31G** algorithm was employed to optimize the molecular geometry and to calculate local molecular parameters regarding effective energy and electron transfer amount. The mechanistic analysis shows that the ability of the hydroxyl oxygen and hydrogen atom to donate or accept additional electron charges is an important property affecting the chemical activity of the thyroid hormone. The derived regression model was shown to have a good statistical performance and could be used to predict the thyroid hormone activity of other HO-PBDE congeners for which experimental measurements are not possible or are restricted. Therefore, the model has the potential to be a useful tool in the application of integrated testing strategies.