Thyroid hormones (THs) have many effects on the cardiovascular system including cardiac hypertrophy. Though THs induce cardiac hypertrophy, the mechanism through which they exert this effect is unknown. We previously found that THs activate signaling related to increased protein synthesis (mTOR and p70 S6 kinase) in the heart. It is unknown whether this activation contributes to TH-induced hypertrophy or if it is merely incidental. In this study, we used rapamycin to inhibit mTOR function in mice and neonatal cardiomyocyte cultures (NCM) treated with THs to test if mTOR/S6 kinase signaling is involved in TH-mediated cardiac hypertrophy. C57 mice were treated with T4 for 3 days, 1 week, 2 weeks, or 1 month with either placebo, T4 (50 µg/100 g body weight/day), rapamycin (200 µg/100 g body weight/day) or T4/rapamycin by subcutaneous slow release pellets. At the end of the treatment period, hemodynamics and physical data were collected and hearts were frozen for Western blot analysis or myocytes were isolated. The effects of T3 and rapamycin were also investigated using neonatal cardiomyocytes. THs activated specific components of the AKT signaling pathway in vivo and in vitro. THs induced cardiac hypertrophy, which was completely inhibited by rapamycin. Our results suggest that TH-induced hypertrophy is mediated by AKT/mTOR/S6 kinase signaling, which is important in the regulation of protein synthesis, a hallmark of cardiac hypertrophy.