Background Sepsis-induced myocardial injury (SIMI) is caused by a variety of mechanisms. The aim of the study is to investigate the effects of metalloproteinase-8 (MMP-8) on SIMI and its mechanisms in rats. Methods Forty male Sprague Dawley rats were randomly divided into four groups: MMP-8 inhibitor (M8I), dexamethasone (DEX), sepsis, and sham groups. The sepsis model was established by cecal ligation and puncture (CLP). Rats in the M8I group immediately received an intraperitoneal injection of M8I (0.1 mg/kg) after CLP. Rats in the DEX group immediately received an intraperitoneal (IP) injection of DEX (2 mg/kg). Rats in the sepsis and sham groups received intraperitoneal injections of normal saline. Rats were sacrificed 12 hours after CLP. Paraffin sections were stained with hematoxylin and eosin to observe the myocardium. The myocardial ultrastructure was observed with transmission electron microscopy. MMP-8, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) were detected by immunohistochemistry. The expression of MMP-8 was measured by Western blotting. TNF-alpha and IL-1 beta levels in serum and myocardial tissue were determined by enzyme-linked immunosorbent assay. Results Compared with the sham group, the myocardium in the sepsis group was seriously injured. MMP-8, TNF-alpha and IL-1 beta expression was higher in the sepsis group than in the sham group. Treatment with M8I or DEX, however, attenuated sepsis induced histopathological changes in the heart, and was associated with significant reductions in serum and myocardial levels of TNF-alpha and IL-1 beta (P <0.05). M8I significantly inhibited MMP-8 expression in myocardial tissue (P <0.05). In addition, treatment with DEX was not associated with a change in myocardial levels of MMP-8 (P >0.05). Conclusion MMP-8 inhibitor attenuated myocardial injury in septic rats, which might be related to reduced expression of TNF-alpha and IL-1 beta.