We examine the effect of rosmarinic acid (RA) in chemical hypoxia-induced injury in rat hepatocytes. Cell viability was significantly decreased by cobalt chloride ($CoCl_2$), a well-known hypoxia mimetic agent in a time- and dose- dependent manner. RA pretreatment before exposure to $CoCl_2$ significantly attenuated the $CoCl_2$-induced decrease of cell viability. Additionally, pretreatment with RA potentiated the decrease of Bcl-2 expression and attenuated the increase of Caspase-3 expression by $CoCl_2$. $CoCl_2$ treatment resulted in an increase of intracellular ROS generation, which is inhibited by RA or N-acetylcysteine (NAC, a ROS scavenger), and p38MAPK phosphorylation, which is also blocked by RA or NAC. $CoCl_2$-induced increase of Bax/Bcl-2 ratio and Caspase-3 expression was attenuated by RA, NAC and SB203580 (p38MAPK inhibitor). $CoCl_2$-induced decrease of cell viability was also attenuated by RA, NAC and SB203580 pretreatment. Additionally, RA inhibited $CoCl_2$-induced COX-2 expression and prostaglandin E2 ($PGE_2$) secretion. Similar to the effect of RA, both NAC and NS-398 (COX-2 inhibitor) blocked $CoCl_2$-induced COX-2 expression and $PGE_2$ secretion. NS-398 attenuated not only $CoCl_2$-induced increase of Bax/Bcl-2 ratio and Caspase-3 expression, but decrease of cell viability. Taken together, RA protects primary cultured rat hepatocytes against $CoCl_2$-induced cell injury through inhibition of ROS-activated p38MAPK and COX-2/$PGE_2$ pathway.