Aralia elata (Miq) Seem is widely used in folk medicine for treating various types of diseases, including diabetes, gastric ulcers, hepatitis and rheumatoid arthritis. The present study investigates the therapeutic effects and possible mechanisms of the total saponins of A. elata (Miq) Seem (TAS) against lipopolysaccharide (LPS)-induced septic cardiac dysfunction and inflammation in mice. Mice were intragastrically administrated with TAS (35, 70 and 140 mg kg⁻¹) for one week before LPS challenge (10 mg kg⁻¹, i.p.). Cardiac injury was evaluated 6 h after LPS induction. Six hours of LPS administration deteriorated cardiac function which was attenuated by TAS pretreatment. TAS attenuated LPS-induced the increase of LDH, CK, AST, and cTnI activities in mice. TAS also ameliorated the imbalance between iNOS and eNOS, as well as preventing NF-κB activation and the subsequent myocardial inflammatory responses in endotoxemic mice. TAS could significantly downregulate LPS-mediated NOX2 expression and ROS production, even though TAS had no effect on LPS-activated TLR-4. The effects of TAS were closely associated with PI3K/AKT and MAPK signaling pathways, as characterized by TAS-induced activation in phospho-Akt and inhibition in phospho-ERK1/2, phospho-JNK, and phospho-P38. Besides, TAS also extended the lifespan of the toxemic mice. These results showed that TAS significantly attenuated LPS-induced cardiac dysfunction and production of inflammatory mediators by inhibiting NF-κB activation, indicating TAS as a potential therapeutic agent for septic cardiac dysfunction.