Aberrant re-activation of transcription factors occurs frequently in cancer. Recently, we found the basic helix-loop-helix transcription factors DEC1 and DEC2 significantly up-regulated in a model of highly aggressive thyroid cancer, raising the hypothesis that these factors might be part of the program driving progression of these tumors. Here, we investigated for the first time the function of DEC1 and DEC2 in thyroid cancer. Using both gain- and loss-of-function approaches, we showed that DEC1 more than DEC2 sustains progression of thyroid cancer by promoting cell growth and invasiveness. We demonstrated that DEC1 controls NOTCH1 expression and that the interplay with the NOTCH pathway is relevant for DEC1 function in thyroid cancer. We confirmed this observation in vivo showing that DEC1 expression is a specific feature of tumor cells, that this transcription factor is significantly over-expressed in all major thyroid cancer histotypes and that its expression correlated with NOTCH1 in these tumors. Finally, we performed RNA-sequencing to define the DEC1-associated gene expression profile in thyroid cancer cells and we discovered that DEC1 drives the expression of many cell cycle-related genes, uncovering a potential new function for this transcription factor in cancer.