Intracellular pathogens of Salmonella spp. survive and replicate within the phagosomes, called Salmonella-containing vacuoles (SCVs) inside macrophages by manipulating phagosomal maturation and phagolysosome formation. While controversies exist about the phagosomal traffic of Salmonella Typhimurium, little studies were carried out with the intracellular survival mechanisms of Salmonella Typhi (S. Typhi). We had previously reported that a eukaryote-like serine/threonine kinase of S. Typhi (T4519) contributes to survival within macrophages and activates host pro-inflammatory signaling pathways regulated by NF-κB. However, neither the mechanisms underlying NF-κB activation nor how it contributes to intracellular survival of S. Typhi were studied. Here we show, by using antibody-mediated blocking and gene knockdown studies that T4519 activates Toll-like receptor 2 (TLR2) signals in the human monocyte-derived macrophages. We computationally predicted the NH2-terminal glycine rich repeat domain of T4519 as the TLR2-binding moiety and confirmed the interaction by co-immunoprecipitation experiment. TLR2-T4519 interaction transcriptionally repressed cystatin B, a cathepsin B inhibitor, leading to the activation of cytosolic cathepsin B, leaked from the lysosomes of the infected cells. Through a series of RT-qPCR, western blotting, gene knockdown, flow cytometry and confocal microscopy experiments, we have shown that active cytosolic cathepsin B cleaves IKB-α, resulting in nuclear translocation of NF-κB and transactivation of its target genes, including reactive oxygen species (ROS), which in turn induces lysosomal membrane permeabilization (LMP). TLR2-dependent targeting of the cystatin B-cathepsin B-NF-κB-ROS pathways by T4519, leading to LMP promotes phagosomal survival of S. Typhi. This study describes a unique mechanism of the exploitation of host NF-κB signaling pathways by bacterial pathogens to promote its own persistence within macrophage cells.