In the present study, we demonstrate that (i) propofol inhibits LPS-induced increased TNF-α production in cardiomyocytes, (ii) the inhibitory effect of propofol on TNF-α production in cardiomyocytes relies on its ability of suppressing the activity of NADH oxidase to decrease the generation of O2− and phosphorylation of p38 MAPK and ERK1/2, (iii) propofol alleviates myocardial dysfunction in mice with endotoxemia, and (iv) propofol protects mice with endotoxemia from death. Here, MAPK3 is linked to serum lipopolysaccharide activity.