Bacterial effector molecules are crucial infectious agents that can cause pathogenesis. In the present study, the pathogenesis of toxic Salmonella enterica serovar Typhi (S. Typhi) proteins on the model host Caenorhabditis elegans was investigated by exploring the host's regulatory proteins during infection through the quantitative proteomics approach. Extracted host proteins were analyzed using two-dimensional gel electrophoresis (2D-GE) and differentially regulated proteins were identified using MALDI TOF/TOF/MS analysis. Of the 150 regulated proteins identified, 95 were downregulated while 55 were upregulated. The interaction network of regulated proteins was predicted using the STRING tool. Most downregulated proteins were involved in muscle contraction, locomotion, energy hydrolysis, lipid synthesis, serine/threonine kinase activity, oxidoreductase activity, and protein unfolding. Upregulated proteins were involved in oxidative stress pathways. Hence, cellular stress generated by S. Typhi proteins in the model host was determined using lipid peroxidation as well as oxidant and antioxidant assays. In addition, candidate proteins identified via extract analysis were validated by western blotting, and the roles of several crucial molecules were analyzed in vivo using transgenic strains (myo-2 and col-19) and mutant (ogt-1) of C. elegans. To the best of our knowledge, this is the first study to report protein regulation in host C. elegans exposed to toxic S. Typhi proteins. It highlights the significance of p38 MAPK and JNK immune pathways.