Immune cells require a fast and effective response to combat invading bacterial pathogens. This response relies heavily on rapid protein synthesis and subsequent trafficking to mediate pathogen suppression. A spatiotemporal understanding of proteome-wide rewiring in response to an intracellular pathogen is currently lacking. By combining click-chemistry with pulsed stable isotope labelling of amino acids in cell culture (pSILAC), we generated the first multidimensional proteomic dataset of host cells (macrophages) infected with Salmonella enterica Typhimurium (STm). Within this rich resource, we detected an aberrant localisation of lysosomal proteases at a late infection stage and reveal that nuclear cathepsin activity correlates with signatures of cell death. Furthermore, pharmacological cathepsin inhibition suppressed caspase-11 dependent macrophage cell death, thus demonstrating an active role for cathepsins during STm induced pyroptosis. This work highlights the utility of resolving the newly synthesised host proteome throughout time and space to drive the discovery of novel biological mechanisms governing host-microbe interactions.