Caspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation and proliferation. Complementary to genetic approaches, small molecule inhibitors have emerged as useful tools for modulating caspase activity. Achieving high selectivity remains a central challenge for caspase-directed inhibitor development efforts, due to the high sequence and structure homology of all twelve human caspases. Here, using a chemoproteomic approach, we first identify a highly reactive non-catalytic cysteine that is unique to caspase-2. By combining both gel-based activity-based protein profiling (ABPP) and a TEV activation assay, we then identify covalent lead compounds that react preferentially with this cysteine and afford a complete blockade of caspase-2 activity. Inhibitory activity is restricted to the zymogen or precursor form of monomeric caspase-2, with compound treatment blocking intramolecular caspase interactions. Focused medicinal chemistry combined with chemoproteomic target engagement analysis in lysates and in cells yielded both caspase-2 selective and promiscuous caspase inhibitors, together with structurally matched inactive control compounds. Application of this focused set of tool compounds to stratify caspase contributions to activation of intrinsic apoptosis indicate likely compensatory caspase-9 activity driving etoposide-mediated cell death in the context of caspase-2 inactivation. More broadly, our study highlights the utility of targeting non-conserved and non-catalytic cysteine residues for achieving improved selectivity profiles for highly homologous families of enzymes.