Oxidative stress is considered an important pathogenic process of cardiac hypertrophy. Lycopene is a kind of carotenoid antioxidant that protects the cardiovascular system, so we hypothesized that lycopene might inhibit cardiac hypertrophy by attenuating oxidative stress. Phenylephrine and pressure overload were used to set up the hypertrophic models in vitro and in vivo respectively. Our data revealed that treatment with lycopene can significantly block pressure overload-induced cardiac hypertrophy in in vitro and in vivo studies. Further studies demonstrated that lycopene can reverse the increase in reactive oxygen species (ROS) generation during the process of hypertrophy and can retard the activation of ROS-dependent pro-hypertrophic MAPK and Akt signaling pathways. In addition, protective effects of lycopene on the permeability transition pore opening in neonatal cardiomyocytes were observed. Moreover, we demonstrated that lycopene restored impaired antioxidant response element (ARE) activity and activated ARE-driven expression of antioxidant genes. Consequently, our findings indicated that lycopene inhibited cardiac hypertrophy by suppressing ROS-dependent mechanisms.