This study examined whether or not the ER stress and Bcl-2 proteins are linked to the protective effect of kaempferol, a phytoestrogen, on ischemia-reperfusion (I/R)-induced cardiac damage. In order to determine if kaempferol modifies the I/R-induced response in H9c2 cardiac muscle cells, the cells were exposed to kaempferol followed by ischemia 12h/reperfusion 4h. kaempferol had a protective effect on the apoptosis induced by I/R in the cardiac muscle cells. The Kaempferol treatment significantly increased the expression level of the anti-apoptotic protein, Bcl-2, but decreased the level of the pro-apoptotic protein, bax. Kaempferol down-regulated the expressions of the endoplasmic reticulum (ER) stress proteins, GRP78, ATF-6alpha, XBP-2, IRE1-alpha, phosphor-eIF-2alpha and CHOP. In ex vivo-Langendorff experiment, the kaempferol treatment regulated the expression of ER stress proteins-CHOP and GRP78. The kaempferol also improved the post-ischemic LVEDP and LVDP significantly after 20, 30, 40 and 50 min of reperfusion compared with the untreated control hearts, which shows that kaempferol offers protection against I/R-associated cardiac dysfunction.