Obesity-induced cardiomyopathy involves chronic and sustained inflammation. The toll-like receptor 4 (TLR4) signaling pathway can associate innate immunity with obesity. Myeloid differentiation primary response 88 (MyD88), an indispensable downstream adaptor molecule of TLR4, has been reported to mediate obesity complications. However, whether inhibition of MyD88 can mitigate obesity-induced heart injury remains unclear. LM8, a new MyD88 inhibitor, exhibits prominent anti-inflammatory activity in lipopolysaccharide-treated macrophages. In this study, the protective effects of LM8 on a high-fat diet (HFD)-induced heart injury were assessed in a mouse model of obesity. As suggested from the achieved results, LM8 treatment alleviated HFD-induced pathological and functional damages of the heart in mice. Meantime, the treatment of mice with LM8 could significantly inhibit myocardial hypertrophy, fibrosis, inflammatory cytokines expression, and inflammatory cell infiltration induced by HFD. Besides, LM8 administration inhibited the formation of MyD88/TLR4 complex, phosphorylation of ERK, and activation of nuclear factor-κB induced by HFD. According to the achieved results, MyD88 inhibitor LM8 ameliorated obesity-induced heart injury by inhibiting MyD88-ERK/nuclear factor-κB dependent cardiac inflammatory pathways. Furthermore, targeting MyD88 might be a candidate of a therapeutic method to treat obesity-induced heart injury.