Endoplasmic reticulum stress results from the accumulation of misfolded proteins and is associated with various pathologies including diabetes and myeloma. ER stress is therefore an area of biomedical interest as its therapeutic intervention can lead to the regression of various disease etiologies. Caspase have been implicated in playing a role in ER stress however their exact mechanisms of action, the substrates associated with their activity and how these enzymes play a role in initiating cell death has remained elusive. Here, we describe a quantitative kinetic analysis of the transcriptional, translational and proteolytic substrate profile for the caspase-specific response associated with induction of ER stress. Our comprehensive analysis revealed the transcriptional profile for all human genes, protein abundance dynamics for 4,476 proteins, and identified 445 caspase substrates thus providing an in depth characterization of the biological response to ER stress. This data provides the cell death community with a valuable resource that can be downloaded for further interrogation. Based on these datasets we found that many caspase substrates are down regulated at the protein level during ER stress. These results suggest that caspase activity inhibits the cellular function of these substrates. Additionally, RNA sequencing revealed a newly defined role for caspases in regulating ER stress-induced transcriptional pathways. This study provides unique insight into the progression of the UPR and the transition into cell death in response to ER stress, which may help identify additional therapeutic strategies to treat ER stress-related disease pathologies.