GRP78 (glucose regulated protein 78) is a major Endoplasmic Reticulum (ER) chaperone that plays a pivotal role in normal ER functioning. Its increased expression also works as an indicator of ER stress. Its anti-apoptotic and pro-autophagic activity makes it an intriguing target to study the relationship between GRP78 and p53, which is also a major regulator of apoptosis and autophagy. Here, we studied the effect of Rotenone and Parathion on human lung cancer cells (A549 cell line) specifically with respect to ER stress and its association with different cell death pathways. In our study, we observed that both compounds increase reactive oxygen species (ROS) generation, down regulate mitochondrial membrane potential (MMP) and affect DNA integrity. Our results indicate that Parathion causes ER stress, up regulates the expression of GRP78, leads to nuclear localization of p53 and induces autophagy while Rotenone down regulates GRP78, causes cytoplasmic localization of p53 and inhibits autophagy. Therefore, it may be concluded that GRP78 affects p53 localization which in turn regulates autophagy.