OBJECTIVES: To explore the expression levels and the potential regulatory mechanism of miR-21-5p in LPS-treated H9c2 cells. METHODS: The secretions of the inflammatory cytokines induced by LPS in H9c2 cells were evaluated using ELISA. We used RT-RCR and western blot to measure the relative mRNA and protein expression levels in LPS-treated H9c2 cells. CCK-8 and EdU assays showed the viability and proliferation profiles of the H9c2 cells. TUNEL assays demonstrated the apoptotic behaviors of the H9c2 cells, and a luciferase reporter analysis was used to investigate the interactions between miR-21-5p and programmed cell death protein 4 (PDCD4). RESULTS: LPS induced damage to the H9c2 cells by reducing the cell viability and down-regulating miR-21-5p. On the other hand, miR-21-5p overexpression inhibited the LPS-induced inflammatory damage in the H9c2 cells. Moreover, PDCD4 was verified as a downstream target gene of miR-21-5p, and its expression was inhibited by the higher miR-21-5p content. Finally, miR-21-5p inhibited septic processes, and the PDCD4 overexpression rescued the miR-21-5p effect in the LPS-treated H9c2 cells. CONCLUSION: Our findings suggest that miR-21-5p inhibits the LPS-induced progression of sepsis in H9c2 cells. Additionally, PDCD4 is a downstream target gene of miR-21-5p, and both molecules serve as potential therapeutic targets for heart sepsis patients.