Oxygen glucose deprivation/re-oxygenation (OGD/R)-mediated ischemia of kidney is frequently leads to enhanced apoptosis and amplified inflammatory response. Sappanchalcone (Sap) is a flavonoid compound that extracted from Caesalpinia sappan L. with a range of cell-protective activities. Herein, we primarily reconnoitered the influence of Sap in HK-2 cells under OGD/R treatment. In this research, the consequence revealed that Sap might linked with ischemia of kidney. Besides, Sap lessened OGD/R-mediated HK-2 cell injury by boosting cell viability, inhibiting apoptosis and inflammation. In addition, Sap hindered activation of the TNFRSF1A/NF-kB signaling. Moreover, upregulation of TNFRSF1A diminished the repressive influence of Sap on OGD/R-mediated apoptosis and inflammation. In conclusion, Sap declined the OGD/R-induced HK-2 cell injury by downregulation of TNFRSF1A/NF-kB signaling, thereby offered a theoretical basis for the handling of ischemia of kidney.