Background <p>This study primarily aims to explore the association between miR-92a-3p and the pathogenesis of septic cardiomyopathy (SCM).</p> Methods <p>To model SCM-induced injury, lipopolysaccharide (LPS) was administered to mice and H9c2 cardiomyocytes. In the in vivo mouse model, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were quantified via echocardiography. Serum levels of myocardial injury markers (CK-MB/cTnI) and cardiac levels of inflammatory factors (IL-6/IL-1β/TNF-α) were measured using ELISA. For the in vitro cell model, cell proliferative capacity was assessed via CCK-8 assay, and the apoptotic rate was evaluated via flow cytometry. The concentrations of pro-inflammatory factors secreted by H9c2 cells and the levels of intracellular oxidative stress markers (ROS/MDA/SOD) were determined using ELISA and commercial kits. The binding interaction between miR-92a-3p and Dusp1 was confirmed via RNA immunoprecipitation and dual luciferase reporter gene assays.</p> Results <p>Inhibition of miR-92a-3p leads to a significant increase in LVEF and LVFS, while concurrently decreasing the levels of CK-MB, cTnI and inflammatory factors. In H9c2 cells, inhibition of miR-92a-3p results in a significant reduction in apoptosis rate and the expression level of Bax. Concurrently, downregulation of miR-92a-3p suppresses the reduction in cell proliferation. Furthermore, downregulation of miR-92a-3p significantly inhibits the excessive synthesis of pro-inflammatory factors, ROS, and MDA. Dusp1 is a potential target of miR-92a-3p. In LPS-induced cells, downregulation of Dusp1 attenuates the cytoprotective effect mediated by miR-92a-3p inhibitors.</p> Conclusions <p>In SCM, upregulation of miR-92a-3p promotes cardiomyocyte apoptosis, inflammatory response and oxidative stress, and exacerbates cardiac dysfunction by inhibiting Dusp1.</p>