We previously demonstrated that 3,4,5-trihydorxycinnamic acid (THC), a derivative of hydroxycinnamic acids, possesses protective effect in lipopolysaccharide (LPS)-induced endotoxemia models. However, the effects of THC in LPS-induced septic kidney are still unclear. Therefore, the present study was carried out to examine the effects of THC in LPS-challenged septic kidney using mesangial cell line and Balb/c mice. THC pretreatment effectively inhibited LPS-induced macrophage infiltration and the secretion of pro-inflammatory cytokines in the kidney of LPS-challenged animals. Pretreatment of rat mesangial cells with THC significantly attenuated LPS-induced PGE2 production and COX-2 expression. THC also significantly suppressed LPS-induced expression of MCP-1 in LPS-activated septic kidney and rat mesangial cells. In addition, THC significantly attenuated LPS-induced degradation of IκB-α in LPS-induced rat mesangial cells. THC also increased the expression of heme oxygenase-1 (HO-1) in LPS-challenged septic kidney and mesangial cells. Multiple signaling pathways including p38 and AKT have been observed to be involved in the THC-induced activation of HO-1 expression. The present data clearly demonstrate that THC protects LPS-challenged septic kidney by decreasing macrophage infiltration and increasing HO-1 expression, suggesting that THC might be a valuable therapeutic agent for compromised kidney in sepsis.