Flavonoids possess several biological and pharmacological activities. Quercetin (Q), a naturally occurring flavonoid, has been shown to downregulate inflammatory responses and provide cardioprotection. However, the mechanisms behind the anti-inflammatory properties of Q in cardiac cells are poorly understood. In inflammation, nitric oxide (NO) acts as a proinflammatory mediator and is synthesized by inducible nitric oxide synthase (iNOS) in response to pro-inflammatory agents such as lipopolysaccharide (LPS), a causative agent in myocardial depression during sepsis. In the present study, we evaluated the protective effect of Q on rat cardiac dysfunction during sepsis induced by LPS. Pretreatment of H9c2 cardiomyoblasts with Q inhibited LPS-induced iNOS expression and NO production and counteracted oxidative stress caused by the unregulated NO production that leads to the generation of peroxynitrite and other reactive nitrogen species. In addition, Q pretreatment significantly counteracted apoptosis cell death as measured by immunoblotting of the cleaved caspase 3 and caspase 3 activity. Q also inhibited the LPS-induced phosphorylation of the stress-activated protein kinases (JNK/SAPK) and p38 MAP kinase that are involved in the inhibition of cell growth as well as the induction of apoptosis. In conclusion, these results suggest that Q might serve as a valuable protective agent in cardiovascular inflammatory diseases.