Myocarditis is a serious hazard to human life and is difficult to treat due to the proliferation of inflammatory lesions in the myocardium. Leonurine (LE) is a plant phenolic alkaloid extracted from Herba leonuri that has demonstrated cardioprotective effects in many preclinical experiments. However, whether LE can be used for myocarditis therapy has not been reported. We aimed to investigate the cardioprotective effects of LE on lipopolysaccharide (LPS)-induced myocarditis in vivo and vitro. The possible mechanism involved was also further elucidated. In vivo, C57BL/6 mice were exposed to LPS with or without LE. We found out that LE effectively improved cardiac function and attenuated cardiomyocyte apoptosis in mice with myocarditis. In addition, LPS-induced inflammatory and oxidative injuries in the myocardium were also reduced by LE administration. In vitro, LPS simultaneously induced apoptosis and reduced the H9c2 cells viability, followed by elevation of intracellular reactive oxygen species (ROS) generation. However, the abnormalities mentioned were preventable by LE pretreatment in a dose-dependent manner. Both in vivo and in vitro, LPS activated the nuclear factor kappa B (NF-кB) signaling pathway in myocarditis, and LE inhibited the increased expression of phosphorylated iκBα and p65 (p-iκBα, p-p65). Furthermore, the nuclear translocalization and nuclear protein expression of p65 in LPS-injured H9c2 cells were also suppressed by LE. Our results demonstrated that LE exerts potent cardioprotective effects against myocarditis via anti-inflammatory and antioxidative mechanisms, possibly through blocking the activation of NF-кB pathway.