Thyroid hormone (TH) is a key regulator of cardiac metabolism. While hypothyroidism is known to result in adverse cardiac effects, the molecular mechanisms that modulate TH signaling are not completely understood. Mediator is a multiprotein complex that coordinates signal dependent transcription factors with basal transcriptional machinery. Mediator complex protein, MED13, was previously demonstrated to repress numerous thyroid receptor (TR) response genes in the heart. Furthermore, we have previously demonstrated that mice overexpressing cardiac MED13 (MED13cTg) treated with propylthiouracil (PTU), an inhibitor of T3 biosynthesis, were resistant to PTU-dependent decreases in cardiac contractility. Here we demonstrate that MED13 expression is induced in the hearts of mice in response to a PTU diet. To elucidate the role of MED13 in transcriptional regulation of cardiac TH signaling, cardiac-specific Med13 knockout mice (MED13cKO) and control mice were placed on a PTU diet or normal chow diet for 4 weeks. An additional group of mice on PTU diet were treated acutely with thyroid hormone (T3). While heart weight to body weight ratios did not differ between genotypes, RNA sequencing was performed from hearts of these mice to understand the role of MED13 in TR-dependent transcription. Echocardiography was performed to assess cardiac function in these mice. In addition, histology was performed to evaluate cardiac structure and fibrosis. These studies demonstrate that MED13 is induced in response to hypothyroidism and further deciphers molecular mechanisms of MED13 regulation of TR-dependent transcription.