Quercetin is the most consumed flavonoid present in fruits and vegetables. There has been increased interest in the possible health benefits of Quercetin and other flavonoids. Because it is reported that these compounds have some antithyroid properties, we were interested if, and by what mechanism, Quercetin might regulate thyroid cell growth and function. In this report we show that Quercetin inhibits thyroid cell growth in association with inhibition of insulin-modulated phosphatidiylinositol 3-kinase (PI3K)-Akt kinase activity. Furthermore Quercetin decreases TSH-modulated RNA levels of the thyroid restricted gene sodium/iodide symporter (NIS). We associated down-regulation of NIS RNA levels with inhibition of iodide uptake at comparable Quercetin concentrations and could show that the inhibitory effect of Quercetin on NIS RNA levels and iodide uptake is reproduced by inhibitors of the PLA₂/lipoxygenase pathway. The specific inhibitor of PKA, H89, only partially inhibited TSH-increased NIS expression and did not reproduce the Quercetin effect. The Quercetin studies thus reveal that the PLA₂/lipoxygenase pathway appears to play an important role in TSH regulation of NIS gene expression, whereas Quercetin inhibition of growth appears to involve an effect on insulin/IFG-1-Akt signaling. The data raise the possibility that Quercetin may be a novel disruptor of thyroid function, which has potential effects on, or use in, the therapy of thyroid diseases.