Background: Sepsis is a systemic inflammatory response usually correlates with multiorgan dysfunction. Myocardial dysfunction is one of adverse outcomes in septic patients resulted in high mortality rate. Aim: To study the impact of irbesartan on TLR4 in attenuation of cardiac depression during polymicrobial sepsis via modulation of p38MAPK/NF-κB signaling. Methods and materials: Polymicrobial sepsis induced via cecal ligation and puncture model (CLP), in 8-12 weeks age albino mice, 1 hr prior to CLP mice were treated with IP irbesartan (3mg/kg). Twenty four hours post CLP hemodynamic parameters including: heart rate, ejection fraction, LVEDP, LVSP and cardiac output, were carried out using micro-tipped transducer catheter. Plasma levels of proinflammatory cytokines, including TNF-α, IL-1β and IL-6, chemokine MCP-1 and cTn-I were measured via ELISA analysis. Phosphorylation degree of P38 MAPK and NF-κB carried out through western blot technique. Results: Hemodynamic parameters showing that irbesartan pretreated group had significantly (p<0.05) elevated ejection fraction, LVSP and cardiac output and significantly (p<0.05) decreased in heart rate and LVEDP as compared with vehicle and CLP groups. Proinflammatory cytokines (TNF-α, IL-1β and IL-6), MCP-1 and cTn-I were significantly (p<0.05) lower in irbesartan pretreated group than vehicle and CLP groups. Western blot analysis shows that phosphorylation degree of p38 MAPK and NF-κB in irbesartan pretreated group were significantly (p<0.05) lower than vehicle and CLP groups. Conclusion: Irbesartan can attenuate the cardiac dysfunction during polymicrobial sepsis possibly via a reduction of proinflammatory cytokines through modulation of both p38MAPK and NF-κB activation.