Cardiac dysfunction is a critical event during sepsis/septic shock. Tanshinone IIA (TIIA), a compound extracted from herb medicine Danshen, has been shown possessing anti-inflammatory and anti-oxidative properties. It is possible, therefore, that treatment with TIIA may attenuate cardiac dysfunction during sepsis/septic shock through inhibition of inflammation. To test this possibility, we preadministrated C57BL/6 mice with TIIA prior to lipopolysaccharide (LPS) challenge. LPS significantly suppressed left ventricular function as evidenced by decreases in EF% and FS% in mice. However, TIIA pretreatment significantly attenuated cardiac dysfunction following LPS challenge. Furthermore, TIIA markedly attenuated the LPS-induced upregulation of circulating tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels. Meanwhile, LPS challenge significantly increased myocardial reactive oxygen species (ROS) production, which was attenuated by TIIA. Moreover, TIIA treatment dramatically decreased the level of the Nox2, reduced phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) expression. In conclusion, TIIA effectively improves cardiac function during endotoxemia in mice. This is attributed to TIIA reducing inflammatory cytokines release and inhibiting the Nox2 signaling during endotoxemia. Display omitted •Tanshinone IIA attenuated the LPS-induced cardiac dysfunction and inflammatory response in mice.•Tanshinone IIA had a regulatory effect on the ratio of iNOS to eNOS in myocardium following LPS challenge.•Tanshinone IIA decreased the level of Nox2 and reduced phosphorylation levels of ERK1/2 and p38 MAPK.